

LIBRARY OF CONGRESS. 

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UNITED STATES OF AMERICA. 




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No. 10 IN THE PHYSICIANS' AND STUDENTS' READY 
REFERENCE SERIES. 



FEVER: 



ITS PATHOLOGY AND TREATMENT 
BY ANTIPYRETICS. 



BEING AN ESSAY WHICH WAS AWARDED THE 

BOYLSTON PRIZE OF HARVARD 

UNIVERSITY, JULY, 1890. 



HOBART AMORY HARE, M.D., B.Sc., 

Clinical Professor of Diseases of Children and Demonstrator of Therapeutics in the 

University of Pennsylvania; Physician to St. Agnes' Hospital and to the Children's 

Dispensary of the Children's Hospital ; Laureate of the Koyal Academy of 

Medicine in Belgium and the Medical Society of London, etc. 

/ A 










vp* 



Philadelphia and London : 

F. A. DAVIS, PUBLISHER. 
1891, 



Entered according to Act of Congress, in the year 1891, by 

F. A. DAVIS, 

In the Office of the Librarian of Congress at Washington, D. C, U. S. A. 



Philadelphia : 

The Medical Bulletin Printing House, 

1231 Filbert Street. 



THIS ESSAY IS DEDICATED 

BY THE AUTHOR TO 

LECTURER ON CLINICAL AND OPERATIVE SURGERY AND EMERGENCY 

SURGERY IN THE UNIVERSITY OF PENNSYLVANIA J 

SURGEON TO THE HOWARD HOSPITAL, 

AS AN EVIDENCE OF 

VERY WARM REGARD. 



PREFACE. 



It would be difficult to find any theme about which 
so much has been written in the past ten years as the 
subject with which this essay deals, and a concise sum- 
mary of the conclusions of many of the best observers 
cannot fail to be of value to the busy practitioner, par- 
ticularly when combined with sufficient experimental 
and clinical experience to make the work something 
more than a mere compilation of other people's ideas. 
Not the least important portion of the book is the 
record of untoward effects produced by the various 
drugs considered, and it is interesting to note how 
severe the symptoms often seemed to be, and yet how 
few of the patients so affected died. 

The following is extracted from the minutes of the 
Boylston Prize Committee:— 

By an order adopted in 1826, the Secretary was 
directed to publish annually the following votes :— 

1. That the Board do not consider themselves as 
approving the doctrines contained in any of the disser- 
tations to which premiums may be adjudged. 

2. That in case of the publication of a successful 
dissertation the author be considered as bound to print 
the above vote in connection therewith. 

The title of this essay, when presented to the Boyls- 
ton Prize Committee, early in 1890, was, " The Uses 
and Values of Antipyretics." 

(v) 



FEVER: 

ITS PATHOLOGY AND TREATMENT. 



INTRODUCTION. 

The interest and importance which is very properly 
attached to the use of certain drugs in the treatment of 
pyrexia in man has already led to the production of a 
large number of researches on this subject, some of 
which have been exceedingly valuable from more than 
one point of view, and, curiously enough, that country 
which is at once the youngest and most pushing for 
money, and not science, has been the source from which 
many of our reliable and accurate studies have come. 
The readers of this essay are too well grounded in the 
study of the condition known as fever to make it neces- 
sary for me to detail the studies so far made. Suffice it 
to state that the medical profession are almost univers- 
ally of the opinion that fever is a disorder of calorifica- 
tion depending upon nervous action, said nervous action 
being the result of various causes, such as the presence 
of poisonous materials in the blood, or of perverted 
functional activity. The first of these may be repre- 
sented by the fever of any infectious disease, the second 
by the so-called l^sterical hyperpyrexia. 

Turning from the general question of fever to those 
drugs which combat it, we are met at once by an 
array of synthetically prepared substances which are 
almost without number, and which are derived chiefly 
from the tar found always in close proximity to deposits 

(i) 



2 Fever: its Pathology and Treatment. 

of coal. Though the title of this essay is a sweeping 
one, it is hardly to be supposed that all these drugs 
must be included ; only the more important members 
of the antipyretic group are therefore studied, such as 
antipyrin, antifebrin, phenacetin, thallin, and salicylic 
acid. 

The value of a drug which can decrease high tern- 
perature by influencing heat production alone cannot be 
overestimated, and, while several of the drugs named 
seem to influence this part of the heat apparatus more 
than that portion connected with the dissipation of 
heat, we have no substance which is distinctly and 
solely capable of exercising an inhibitory power over 
the development of heat in the bod}\ 

Frequently, one of the substances put forward by 
its discoverer as a useful antipyretic has been found to 
so depress the heart or the respiration that it cannot be 
used, while another produces secondary lesions in the 
tissues of the body by a more slowly acting influence. 

For both experimental and practical purposes we 
may, therefore, divide antipyretics into three great 
classes, as follows : — 

First. — The substances which allay or prevent fever 
by inhibiting its production. 

Second. — The drugs which possess the power of 
decreasing the production and increasing the dissipation 
of heat. 

Third. — The compounds which allay fever, not by 
* stopping the manufacture of heat-units, but by so in- 
creasing the radiation of heat that the loss is greater 
than the manufacture. 

The first and third classes are directly o imposed to 
each other. The second class is half-way between, and 
it is to this class that most of our antipyretic drugs 



Introduction, 3 

belong. The first class is the ideal ; the second is the one 
we have to be content with; the third is that used by 
our forefathers, and is the most unreliable and harmful, 
since the tissues are quite as rapidly destroyed under 
their influence as they were before the drug was given ; 
the centre of the body remaining in pyrexia, while the 
cool skin and extremities are apt to lead the physician 
into the belief that the fever no longer exists. The 
tissue-waste of the fever goes on unchanged, and the 
patient, if the disease be prolonged or asthenic in char- 
acter, is in almost as serious a condition as if no 
attempt to reduce his temperature had been made. It 
should never be forgotten that hyperpyrexia, or even 
an ordinary fever, is dangerous in two ways, namely, by 
destroying tissue, and thereby reducing vital power, or 
by acting simply as too great bodily heat, and thereby 
producing nervous or cardiac symptoms, such as are 
seen in cases of sun-stroke and heat exhaustion, in 
which the condition of the patient is the result of coagu- 
lation of the cerebral or cardiac protoplasm, or is one 
of depression of all vital function. 

Closely allied to this question is that which asks us 
to define what we mean by hyperpyrexia. As given in 
most works on fever, this term is applied to any state in 
which the temperature reaches 106° or 107° F. ; but in 
reality the figures have nothing to do, except in an in- 
direct way, with what the student or plrysician wishes 
to know. A temperature of 106° F.,in a young, healthy 
man suffering from an acute attack of some short-lived 
disease, does not mean very great danger ; but a tempera- 
ture of 103°, day after day in typhoid fever, does mean 
danger, and must be carefully attended to. In simple, 
continued fever, 106° F. is a hyperpyrexia; in typhoid, 
or other low fever, 103° F. is a hyperpyrexia. The 



4 Fever: its Pathology and Treatment. 

question is not one of actual degrees Fahrenheit, but 
rather as to whether the temperature present is doing 
any harm. 

Returning to the drugs which can be divided into 
classes according to their physiological effects, we m&y 
classify them as follows : — 

1. Those which decrease heat production alone are 
not known. 

2. Those which act both on dissipation and produc- 
tion are antip3 T rin, antifebrin, carbolic acid, salicylic 
acid, similar substances, and quinine. 1 

3. Those which only dissipate heat, as far as we 
know, namely, the great group of cardiac sedatives 
and their allies, such as aconite and antimony. 

No one is more sensible than the writer that this 
arrangement of the subject is partly artificial. In the 
study of these drugs, both experimentally and clini- 
cally, two facts are present which are exceedingly con- 
fusing and almost impossible to separate. Given a 
drug which decreases fever, we find that do what we will 
we cannot invent any accurate apparatus which will 
determine whether the decrease in heat dissipation, 
which accompanies the decrease in production, is the 
result of that decrease in the manufacture of heat, or is 
due to a direct action of the drug upon the function of 
dissipation itself. If we throw water on a fire we know 
that the heat production is decreased, and that the 
giving off of heat must also be decreased ; but if the 
fire and stove be heavily coated with clay we have a 
state in which both the production of heat and the dis- 
sipation are directty interfered with. In the first in- 
stance dissipation is decreased secondarily or indirectly. 

1 In this class also should he placed cold bathing, which probably 
decreases heat production as well as increases dissipation. 



Introduction. 5 

In the second instance dissipation is affected primarily 
and directly. As the relation between these two great 
governing factors in the balancing of bodily temperature 
is difficult of understanding, they may be tabulated to 
make them clear. 

Bodily temperature may be raised by — 

(a) Increased production of heat. 

(b) Decreased dissipation of heat. 

(c) Increased production and increased dissipation, 
the dissipation not keeping pace with production. 

(d) Normal production associated with decreased 
dissipation. 

In any of these instances the temperature of the 
body rises because the heat is made faster than it can 
be dissipated from the surface. On the other hand — 

Bodily heat may be decreased by — 

(a) Decreased production of heat. 

(b) Increased dissipation of heat. 

(c) Increased production and increased dissipation ; 
when the second factor is more active than the first. 

(d) Normal production, with excessive dissipation. 
The actions of most of the drugs which exercise an 

antipyretic influence have been studied upon animals, 
and, although the practical use of all drugs must depend 
on the results obtained by the clinician, much may be 
done by careful researches in the physiological labora- 
tory which discover serious contra-indications and dan- 
gers. The experimental and clinical side of medicine 
should be studied hand in hand, the first saving the 
practitioner from error and giving him a foundation on 
which to base his actions, and the second showing him 
by experience the minor details which it is so necessary 
for him to understand. 

A discussion of the methods resorted to by various 



6 Fever : its Pathology and Treatment. 

experimenters upon fever is not in place here. Suffice 
it to say that some of the most laborious researches 
have been carried out by skilled investigators, only to 
arrive at the most contradictory conclusions. Thus, in 
a very recent essay, showing a vast amount of labor, 
Winternitz, assisted by Paschkis and Pal, 1 has given us 
the results reached by using thermometers applied inside 
of air-tight boxes to the skin, the bulbs of the instru- 
ments being flattened so as to offer a greater surface. 
By this means the production and dissipation of heat 
were measured (?). An} r one who has studied fever knows 
that in certain diseases, though the skin ma} r be cold 
and clammy, the central temperature may be exceedingly 
hio*h ; and it is also a well-known fact that the heat given 
off by the skin varies with every flush of blood which 
goes to and leaves the surface. 

Some years since, Beyer 2 attempted to show, by ex- 
periments made with certain antipyretics upon the blood- 
vessels of the terrapin, that these drugs lowered fever 
by increasing heat dissipation alone, because he found 
that the blood-vessels of the terrapin were dilated by 
these drugs. From such a study this careful observer 
enunciates in italics " that antipyrm lowers temperature 
hy this means." It is such statements that give rise to 
the contradictory turmoil which is continually going on. 
The only accurate method that we can resort to is one 
which will account with mathematical exactitude for 
every unit of heat made or lost. There are two calori- 
meters, so called, which will do this with more or less 
accuracy. 

The first of these is that of d 'Arson val, which simply 
consists of one cylinder within another, the space be- 

1 Zur Pathol, und Hydrotherapie des Fiebers. Leipsic, 1888. 
fl Amer. Jour. Med. Sciences, April, 1886. 



Introduction. 7 

tween being filled with water. An air-tube enters the 
inner compartment to give air to its occupant, and then 
passes into the water in the form of a coil , in order to 
give any heat in the air expired by the animal in the 
inner box to the water before the air escapes into the 
surrounding atmosphere. 

This calorimeter is inaccurate, in that it does not 
prevent the escape of heat from the water, owing to the 
outer cjdinder being uncovered. 

The other calorimeter, which was used by Wood in his 
early studies, is also open to many errors. Arranged, 
as is the d'Arsonval, so far as the passage of the air 
through the box and water is concerned, yet more accu- 
rate, in that the outer C3 T linder or box is protected from 
the atmosphere by hair-packing and a wooden cover, it 
nevertheless is faulty because every time the animal is 
taken out of the box this receptacle must be lifted 
bodily out of its envelope of water, all the air-pipes 
disconnected and the thermometers removed, and an 
air- and water- tight door unscrewed. All these changes 
take time and expose the water in the outer box to the 
atmosphere, while the dripping sides of the inner box, 
by the evaporation of the water, cool it by several de- 
grees, so that when it is returned to its casing of liquid 
it in turn lowers the temperature of the water in the 
tank. Further, if the door be not most carefully ap- 
plied, water leaks into the animal compartment, and the 
experiment is either ruined by the drowning of the dog 
or the chilling of his body. 

These objections, however, no longer exist, having 
been recognized by Dr. Wood and obviated chiefly 
through the ingenuity of Dr. Reichert. 

The Pulse in its Relation to Fever. — For many 
years the profession of medicine have been in the habit 



8 Fever : its Pathology and Treatment 

of "feeling the pulse " with the perfectly proper object 
of determining what the state of the system is, as it ap- 
pears on this sign-board of the body ; but it has only 
been of late, when our knowledge has snpposably in- 
creased, that we have come to consider the pulse-rate 
and force as anything more than a simple aid. At 
present, many seem to forget that the very value of the 
pulse as a sign-board depends on its readiness to obey 
the beck and call of the variations in the system, and to 
consider that in fever, for example, the pulse is rapid 
not because the fever makes a rapid pulse, but that a 
rapid pulse and fever are equally important conditions. 

In other words, these persons regard the rapid pulse 
not as the result of the heightened temperature, but as 
a symptom of itself. 

While in our present state of knowledge concerning 
the poisons which produce fever we cannot assert that 
none of them act on the heart in the same manner as 
does a drug, thus altering the pulse-rate and force, we 
are able by experimentation to prove that high tempera- 
tures, of themselves, do alter the heart-beat, and, in 
addition, that antipyretics, as a general rule, in lowering 
the fever lower the pulse, not directly, but indirectly. 
Such results are to be gleaned from the studies of 
Lauder Brunton and Newell Martin, as well as several 
other workers in this field, who have proved that febrile 
temperatures stimulate the accelerator cardiac nerves. 

Closely associated with this question is that of the 
relationship between arterial pressure and fever. 

It at once becomes evident that if heat stimulates 
the accelerator nerves an increased rapidity of cardiac 
action must ensue, and in consequence an increase in 
the amount of blood thrown into the arteries must re- 
sult ; also that as a consequence of these changes the 



Introduction. 9 

arterial pressure must rise, even if the vasomotor system 
itself responds in no way to the action of the heat. In 
nearly all cases of high fever, unless the system be 
greatly exhausted, the vasomotor apparatus certainly is 
excited to increased activity. 

The Dangers of Fever. — As the dangers of high 
fever have already been spoken of, the impression ought 
not to be given that every one believes, with Lieber- 
meister, in the absolute harmfulness of such states. 
While most of the profession have accepted such views, 
their opponents, while not in large number, have been so 
prominent as individuals that their studies cannot be 
passed by. In 1883 Unverreicht 1 tried to rebut the 
testimony then so rapidly accumulating in favor of anti- 
pyretic measures, and still later Naunyn, 2 in a very 
carefully written and logical paper, has strongly denied 
their value and usefulness. While he grants that high 
temperatures are most important for prognosis and diag- 
nosis, and that certain antipyretic measures do good, 
he nevertheless insists that a raised temperature is an 
index, not a cause, of evil, and that the cold bath does 
good primarily by its effects on the nervous system, not 
by its direct action on the fever. He acknowledges, of 
course, that such temperatures as 108° to 110° F. are 
of dangerous import in themselves. 

The question of the relative action of high fever on 
the body and that of antipyretics is sufficiently im- 
portant to require some thought. To prove that his 
assertions are correct, Naunyn gives the results reached 
in a series of studies made by him on men and animals. 
He found that healthy rabbits will bear an artificially 
induced temperature of 106° to 107° F., rising at times 

1 Deutsche Med. Wochenschrift, 1883, S. 67. 

3 Archiv fur Experimental Path, und Pharmacol., 18, 2 S., pp. 48-124. 

1* 



10 Fever : its Pathology and Treatment. 

to 108° or 109° F., for days together without any injury, 
if plenty of air and drink be given them ; and he was un- 
able, on making autopsies, to find any lesions present as 
a result of the experiment, except a slight cloudiness 
of the renal epithelium. 

It is worth while to call attention to two facts which 
have been apparently overlooked by Nauirvn and many 
of the readers of his paper, namely, that 106° to 107° 
F. are only a few degrees above the rabbit's normal 
heat, which is about 103° F. ; so that the pyretic tem- 
perature of these animals corresponded to but 101° to 
102° F. in man, — a temperature easily borne in many 
fevers. Secondly, it should be remembered that in 
these studies heat was constantly applied to maintain 
the abnormal temperature, and the animal did not 
manufacture the heat itself. Although at first sight 
this seems unimportant, it ought not to be overlooked. 
The tissue changes in the two instances are entirely 
different. To use a humble simile : in the one case the 
stove is kept hot by heat applied to its exterior without 
any combustion of the coal (its tissues) inside of it ; in 
the other case the heat is maintained by the use of the 
coal itself. Yery different changes are naturally found 
in the coal in the two cases. Much more might be said 
of this, but the entire subject may be summed up as 
follows, viz., that while high temperatures are borne in 
some instances with no evil result, the majority of cases 
do not turn out so favorably. 



ANTIPYRIN. 

Experimental Evidence. 

No sooner was this drug placed before the profession 
than numerous trials of its powers were made in the 
laboratory, as well as at the bedside ; so that at the 
present time we have a mass of material in the form of 
reports which is stupendous. 

Heat Functions. — In studying the influence of any 
drug upon bodily heat, the first point which arises 
before us is, whether or not it lowers normal bodily 
temperature. The evidence in regard to this point is 
somewhat contradictory, yet it is possible to bring 
order out of the chaos. As early as the winter of 1885- 
1886, Wood, Reichert, and the writer 1 carried out a 
series of experiments upon this subject. We found 
that, in the animal in which no febrile movement was 
taking place, antipyrin caused a fall of temperature 
amounting to several degrees Fahrenheit. 

These results have been confirmed b} r those of Pav- 
linow 2 and Anserow, 3 the first of whom noted a fall in 
the temperature in normal animals amounting to from 
1° to 2° C. Anserow, using animals free to run about, 
reached results of similar import, in so far as the rectal 
temperature was concerned, although he asserts that 
the surface temperature was raised. The doses of these 
two investigators were, however, enormous, — from 30 to 
100 grains. Umbach 4 has noted a fall in his own normal 

1 Therapeutic Gazette, September, 1886. 

3 Meditzenskoie Obozrenie, fasc. xii, 1885, p. 1203. 

3 Congress of Russian Medicine. Moscow, 1887. 

4 Arch, fur Experiment. Path, und P„harm., xxi. 

(ii) 



12 



Fever: its Pathology and Treatment. 



temperature, amounting to 1.4° C, after having taken 
60 grains twice in two clays, and this is confirmed by 
Jacubowitsch, 1 who found that a fall of temperature 
occurred in healthy children under the influence of 
an ti pyrin. 

Although, at first glance, it would appear from these 
foreign observers, and indeed from the results reached 
in this country, that a very considerable fall takes place, 
there are, nevertheless, several points which close exami- 
nation of these papers brings forth. In the first place, 
a very serious element of fallacy attaches itself to ex- 
periments made upon animals tied down upon tables, or 
animal-holders, simply because such animals lose their 
bodily heat very rapidly under such circumstances. 

This element of fallacy is present in the studies of 
Wood, Reichert, and the writer, and Pavlinow. 

The following experiments emphasize this fact, 
and all pl^siologists recognize that such changes do 
occur : — 

Experiment No. 1. — Dog ; weight, 22£ lbs. Full 
grown 
laboratories, 



Dog tied in a dog-trough such as is used in 



11.45. 


Rectal 


temperature, 


11.50. 


(< 


ic 


12. 


a 


n 


12.10. 


u 


a 


12.20. 


cc 


u 


12.30. 


c< 


M 


12.40. 


ci 


If 


12.50. 


u 


cc 


1.20. 


« 


(< 



102.4 

102.4 

102.3 

102.1 

101.7 

101.8 

101.2 

101. 

100.3 



Experiment No. 2. — Dog ; weight, 32 lbs. 
grown. Tied on table :• 



Full 



4 Jahrbuch fur Kinderheil., 1885, Bd. xxiii, No. 4. 



Antipyrin: Exper 

Rectal temperature, 



imental Evidence. 


103.2 




. 


. 103.1 




, 


. 103.1 




. 


. 103. 




. 


. 102.2 




, 


. 101.9 




. 


. 101.7 




. 


. 101.7 



13 



10.15. 

10.25. 

10.35. 

10.45. 

10.55. 

11. 

11.10. 

11.20. 



Again, in the experiments of Pavlinow, Anserow, and 
Umbach, the amount of the drug given was almost toxic, 
and the result cannot be considered as an effect of a 
medicinal dose. That toxic doses are capable of greatly 
lowering temperature is not only a very likely hypothesis, 
but an established fact. Aside from clinical observations 
made in cases of poisoning, we have the experiments of 
Bouchard, 1 Henocque,2 Arduin, 3 and Huchard, 4 all of 
whom have found that large quantities of antipyrin may 
cause a fall of as much as 6.2° C. 

In order to determine whether all the fall which oc- 
curred was due to the antipyrin or to the constrained 
position of the animal, the writer made two experiments 
on free animals to determine this point, using a some- 
what smaller dose. A slight fall occurred, which did 
not exceed more than one degree. 

Experiment No. S. — Dog ; weight, 20 lbs. Full 
grown. Free to run about room. 



12.05. 
12.06. 
12.10. 
12.15. 
12.20. 
12.30. 
12.40. 



Rectal temperature, 

Gave 4 grains of antipyrin in to jugular vein. 
Rectal temperature, 



103.2 

103.1 
103.0 
102.8 
102.7 
102.2 



1 Comptes Rendus de Soc. Biologie, No. 43. 

3 Gazette Hebdomadaire. 3 These de Paris, 1885. 

4 Societe de Therapeutique. Bulletin, 1885. 



14 



Fever: its Pathology and Treatment. 



12.50. 
1.00. 
1.10. 
1.20. 
1.30. 
1.40. 
1.50. 
2.00. 



Kectal temperature 



102.3 
102.2 
102.1 
102.1 
102.0 
102.3 
102.3 
102.3 



Experiment No. 4- — Dog; weight, 18^ lbs. Full- 
grown. Free to run about. 

Rectal temperature, 103.8 

Gave 4 grains antip} T rin by jugular vein . 
Rectal temperature, 



2.10. 
2.12. 
2.20. 
2.30. 
2.40. 
2.50. 
3.00. 



103.7 
103.2 
103.1 
103.0 
102.8 



It should also be remembered that in the calorimet- 
rical studies of Wood, Reichert, and the writer on 
normal animals a similar fall occurred, and, as these 
dogs were not tied down, the results are confirmatory 
of the conclusions already given. 

There can be no doubt, therefore, that antipyrin in 
ordinary doses may lower the normal bodily tempera- 
ture more or less complete^, according to the amount 
given and the susceptibility of the recipient. 

Calorimetrical Studies. — Owing to the expensive- 
ness and cumbersomeness of the apparatus involved, 
very few investigators have attempted to study the 
effects of antipyrin by this means. 

Three such studies have, however, been published, 
namely, that of Wood, Reichert, and the writer, 1 those 
of P. J. Martin 2 and those of Destree. 3 The last two in- 
vestigators confined their experiments to fevered animals. 



1 Therapeutic Gazette, Sept., 1886. 3 Therapeutic Gazette, 1887. 

3 Journal de Medecine de Bruxelle, July 20, 1888. 



Antipyrin : Experimental Evidence. 15 

In the calorimetrical studies made by the first of 
these investigators upon animals whose temperature was 
normal, it was found that the drug, as a general rule, 
caused a reduction in the temperature, and that the cause 
of this fall was dependent upon a decrease in the pro- 
duction and dissipation of animal heat. In seven out of 
nine studies this phenomenon was produced, but in the 
remaining two, though the bodily temperature fell 
slightty, yet the calorimeter showed an increase in heat 
production and dissipation instead of a decrease, as in 
the others. These two results we ascribed to the fact 
that large doses of antipyrin have been found to be pro- 
ductive of a rise in bodily heat associated with convul- 
sions ; but this explanation is not a satisfactory one, 
for, according to our own studies, a much larger dose 
is needed to cause convulsions than that which we gave 
to produce these variations in body-heat. Further than 
this, the record of the rectal temperature in these cases 
fails to show that an increase in bodily heat occurred. 
Some other cause for these results must, therefore, exist 
than those of which we speak. 

The fact that seven of our nine experiments were 
similar in result shows, however, that the conclusions as 
to the mode of fall may be considered as correct, and it 
is probably true that heat production is primarily 
lessened and followed by a decrease in heat dissipation. 

There are several facts in relation to some of these 
experiments which must be carefully examined into, chief 
among which is the degree of fall in temperature follow- 
ing the ingestion of the drug. As has already been 
pointed out in the early part of this paper, the variation 
in the bodily heat of a dog is so great that a change of 
a fraction of a degree in temperature ought not to be 
regarded as the result of the action of a drug, although 



16 Fever: its Pathology and Treatment. 

it may point toward the general result if the same phe- 
nomena frequently present themselves. Thus, in Ex- 
periment No. 65 of our series the dog's temperature fell 
2.1° F. before the drug was used, and only 1.0° P. after 
it was given ; so that, while the total fall of temperature 
was from 104.4° F. to 101.5° F., more than two-thirds 
of this drop was independent of any effect of the drug. 

This same state of affairs, to a less degree, holds 
good in several of the remaining experiments which are 
detailed. 

Not only do the clinical cases of every one prove 
that antipyrin decreases fever, but in addition the 
studies of Wood, Reichert, and the writer, and those 
of Martin show us that this is the case. Still further con- 
firmation is to be found in the experiments of Girard, 1 
who, puncturing, as did Martin, the corpora striata, 
found that antip} T rin caused a decrease in the resutling 
high temperature. To give a long list of clinical authori- 
ties is, therefore, useless, and the writer will pass from 
the consideration of the influence of antipyrin upon the 
normal animal to that of its effect on the dogs suffering 
from fever, still examining and considering the studies 
of Wood, Reichert, and himself, as they are our chief 
leaders in this question. We concluded that antipyrin 
low r ers fever b}^ the same action as we believe it affects 
the normal temperature, namely, by a primary decrease 
in heat production, followed by a secondary decrease in 
heat dissipation. These conclusions have a better 
basis than their predecessors, and are probably correct. 
Further than this, they are confirmed by the studies of 
Martin, 2 carried out some time later, who finds that 
antipyrin decreases heat production, but increases heat 

1 Revue Med. de la Suisse Romande, 1888. 
3 Therapeutic Gazette, 1887. 



Antipyrin: Experimental Evidence. 17 

dissipation, a discrepancy in result which might well 
occur, in view of the secondary role pla} r ed by heat 
dissipation under such circumstances. Still more re- 
cently Destree, 1 of Brussels, has reached conclusions 
identical with those of Wood, Reichert, and the writer, 
and differing in consequence from those of Martin in the 
particular named. As the last two observers used the 
calorimeter of d'Arsonval, these results may be con- 
sidered as facts which rest on undeniable evidence, since 
the same results are reached by different men using 
different instruments and different methods of producing 
fever. 

Though the much more accurate method of studying 
heat functions has permitted us to make these deduc- 
tions, much has been said by various persons as to 
the effect of antipyrin upon the sweat-glands, and the 
possibility that the fall of temperature depends on the 
profuse sweat produced. That the profuse sweat is not 
responsible for the fall in temperature is proved by a 
very simple experiment which can be tried at any time, 
and which consists in the hypodermic injection of a 
dose of atropine previous to the administration of the 
antipyrin. Although the sweat does not appear, the 
temperature nevertheless falls. 

Bettelheim 2 has attempted to determine the physio- 
logical action of antipyrin by a series of experiments 
in the laboratory of von Basch, which are prostituted 
by the hypothetical conclusions which he draws from 
them. He says : "It is intelligible that when — as fol- 
lows from the elevation of the skin temperature — the 
skin vessels are dilated and the internal blood-vessels — 
as follows from the increased blood-pressure — are con- 

1 Journal de Med. de Chir. et de Pharm., July 20, 1888. 

2 Med. Jahrb. d. K. K. Gesellsch. d. Aerzte in Wien, 1885. 

A 2 



18 Fever: its Pathology and Treatment. 

tracted, a larger quantity of blood streams through the 
skin vessels in a unit of time, and there dissipates its 
heat, so that gradually the entire mass of the blood is 
cooled down." 

This is such a pure hypothesis that no one can 
understand how any one could state it, for he states at 
one and the same time that the skin vessels are dilated 
by the same temperature that contracts the internal 
blood-vessels, and utterly ignores the fact that, as there 
is a mechanism for heat dissipation, so must there also 
be one for heat production. The experiments of Mara- 
gliano 1 with the plethy sinograph of Mosso lead him to 
conclude that antip3 r rin dilates the dermal blood-vessels, 
and he also reaches the same conclusion as do Bettel- 
heim and Murri, 2 and with no more ground for his 
statements asserts that the decrease in temperature is 
due solely to the increased heat dissipation. Be3 r er 3 
has made equally unfortunate statements as a result of 
his studies on the vessels of the tortoise. 

Circulation. — As has already been stated, the close 
association which exists between febrile processes and 
changes in the circulatory system makes their study of 
great interest when drugs are used to lower temperature. 

Referring once more to the studies of Wood, Reichert, 
and the writer, we find a number of experiments bearing 
on these points. Beginning with the normal animal, we 
find that while here, as in the calorimetrical experiments, 
the bodily temperature fell in the normal dog after the use 
of antipyrin, the fall is not accompanied by any changes 
of moment in the circulatory system, as is shown 
when the animal is attached to the manometer and 
kymograph. In the first experiment detailed the tem- 

* Gazz. degli. Osp., 1872-82. 3 Ibid., 1888-91. 

3 Amer, Jour. Med. Sci., April, 1887. 



Antipyrin: Experimental Evidence. 19 

perature progressively fell without any circulatory 
change of moment. In the second the doses were so 
enormous that convulsions were produced almost at 
once, thus making the record practically useless ; and 
in the third the dose was so large that, while at first the 
temperature fell without much change in the circula- 
tion, convulsions ultimately arose and disturbed the 
result. 

The first record is the only one, therefore, which is 
perfectly clear, while the third confirms it, and this 
single instance would seem to show that there is no 
relationship between the fall of temperature and arterial 
pressure. 

Whatever ma}^ be the cause of the changes in normal 
temperature, one thing seems certain, namely, that anti- 
pyrin does not directly influence in any way the circu- 
lation itself, either in fever or health, unless the dose is 
massive and toxic in effect. This seems proved, not 
only by the studies just quoted, but also by the re- 
searches of many others, although some evidence of 
importance points in an opposite direction. 

In more recent studies made \>y the writer alone it 
was proved that doses of from T to 15 grains, when given 
to a dog of 20 or 30 pounds, have no action of impor- 
tance (see tracings Nos. 1 and 2) ; but Pavlinow l asserts 
that the drug causes an increased arterial pressure and 
a slightly slowed and more regular pulse. On the other 
hand, Dujardin-Beaumetz 2 agrees with the writer, and 
asserts very positively that the influence exerted by 
medicinal doses is very slight. 

The reason for Pavlinow 's contradictory results lies 
probably in two points, namety, that the drug used by 

1 Meditzinskoie Obozrenie, fasc. xii, 1885, p. 1203. 

2 Therapeutic Gazette, Sept. 15, 1885. 



20 Fever : its Pathology and Treatment. 

him was impure, as it was not the right color, nor was 
it made by Knorr, and that the doses used may not have 
been medicinal. This is undoubtedly the reason for the 
statements of Arduin 1 and Demme, 2 who used doses 
which were absolutely overwhelming. Thus, Arduin 
gave as much as 45 grains to a rabbit at one dose, and 
Demme gave 15 grains. The first observer noted circu- 
latory depression and cardiac paralysis; the second, 
increased arterial pressure, followed by a fall, although 
the heart continued to act very well. The results of 
Devraux-Armand 3 and of Henri Casimir 4 are identical 
with those just quoted, and depend likewise upon the 
large amounts employed, for there can be no doubt that 
such doses can produce every form of circulatory dis- 
turbance. Notwithstanding these assertions, then, the 
results obtained by those persons using moderate doses 
positively decide that the drug is, in reality, without 
circulatory effect, and that any changes which are seen, 
clinically, depend on the alterations in temperature 
rather than on the drug. 

When given in poisonous doses, the circulatory 
changes and the systemic results produced depend to 
some extent upon the idiosyncrasies of the animal re- 
ceiving the drug. If convulsions occur, the circulation 
is, of course, disturbed, and the heart is finally arrested 
in diastole, being previously much weakened. Arduin 
and Demme assert that this is so in the frog, but Cop- 
pola 5 states that antipyrin has no such influence, and 
that the heart is unaffected in this animal. From the 
studies of the writer he is confident of the correctness 
of the statements of Arduin and Demme, and doubts 

1 Paris Thesis, 132, 1885. 

3 Fortschritte der Medicine, Bd. ii, 1884, p. ti57. 

3 These de Nancy, 1885. * These de Lyon, 1886. 

8 Roberts Jahresbericht, 1885, p. 314. 



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Antipyrin : Experimental Evidence. 21 

those of Coppola, and the results obtained by Batten and 
Bokenham 1 are in direct confirmation of his opinions. 

The Blood. — In no part of the study of the physio- 
logical action of a drug should greater care be taken to 
separate the effects of moderate and medicinal doses 
from those of toxic size, than in respect to this tissue. 
It is the carelessness of investigators in respect to these 
facts which so commonly gives rise to apparently contra- 
dictory results, which are in reality perfectly correct 
and readily adapted to each other. 

There can be no doubt that antipyrin is capable of 
producing changes in the character of the blood, both as 
to its color and its corpuscular elements, provided that a 
sufficient amount be emplo}^ed ; and it is also a fact that 
this amount must always be large enough to pass beyond 
the boundary of a " medicinal dose," and be called a 
toxic amount. While this assertion seems paradoxical 
at the first sight, it is not so, in that in those who exhibit 
cyanosis and other evidences of poisoning, after ordi- 
nary doses, a toxic effect is in reality present, owing 
to idiosyncrasy. In other words, a person who is un- 
usually susceptible to 10 grains of antipyrin is quite as 
much poisoned when this dose is taken as is the indi- 
vidual not so readily affected who exhibits s} 7 mptoms 
of poisoning after 30 or 60 grains. 

That no changes in the haemoglobin occur, under 
doses given for medicinal purposes in ordinary patients 
or animals, seems positive, both by reason of the absence 
of any signs of such troubles and the result of careful 
spectroscopic examination. Thus, Leon Arduin 2 asserts 
that in his studies upon the lower animals no changes in 
the blood could thus be determined, and he is, therefore, 

1 British Med. Jour., June 1, 1889. 

2 Bulletin Ge'n. de The'rap., March 30, 1885. 



22 Fever: its Pathology and Treatment 

in accord with Pavlinow, 1 who finds not only that this 
is so when antipyrin is injected into the veins, bat that, 
in addition, no spectroscopic changes are produced, even 
when a 1-per-cent. solution of antipyrin is added to the 
blood outside the body. The writer has never seen any 
change in the color of the blood of an animal to whom 
medicinal and not toxic doses were given, and Huchard 2 
has reached conclusions of a similar nature. Crolas and 
Hugounenq 3 also found no methaemoglobin in the blood, 
even after the use of from 45 to 150 grains of antipyrin 
a day for forty days. On the other hand, abundant evi- 
dence, both clinical and experimental, exists to prove 
that changes are produced by excessive amounts, par- 
ticularly if any susceptibility is present. Too many 
instances are on record in the case of the human being 
in which c} T anosis and a peculiar coloring of the face 
and surface of the body have occurred to allow of any 
doubt on this point, and the researches of Lepine 4 give 
us ample evidence of the nature of these changes^ for he 
found that the spectroscopic bands of methaemaglobin 
were strongly present in the blood of animals poisoned 
by the drug. 

These points are of more practical bearing in rela- 
tion to therapeutics than would appear at first sight, in 
that certain writers assert that, in their opinion, the 
antipyretic influence of antipyrin depends upon a failure 
on the part of the haemoglobin of the blood to carry to 
the tissues the ox} T gen necessary for their consumption, 
and that the consequent fall in fever is owing to the 
alteration of the haemoglobin into the abnormal product 
already named. 

1 Meditzinskoie Obozrenie, fasc. xii, 1885, p. 1203. 

3 La Semaine Medicale, 1885. 3 Lyon Me'dicale, March 3, 1889. 

4 Lyon Medicale, vol. liii. 



Antipyrin : Experimental Evidence, 23 

If, as has been asserted, 1 the hsematin of the blood 
is separated under the influence of the drug, we should 
have at once the appearance of this substance in the 
urine ; and the fact that hemoglobinuria so rarely, if 
ever, occurs after ordinary doses of antipyrin, proves 
that the drug may lower bodily heat without dissolving 
out or destroying the coloring matter of the blood. 

The effect of antipyrin in ordinary amounts on the 
corpuscles themselves is of no moment, but changes 
naturally occur in these bodies when their coloring 
matter is destroyed or altered. Under such circum- 
stances they appear somewhat shriveled, and, perhaps, 
crenated, but otherwise normal. That they are not 
much affected is proved by the researches of Crolas 
and Hugounenq, 2 and by those of Pisemski, of St. 
Petersburg. 3 The first-named investigators found that, 
even when from 40 to 150 grains of antipyrin are given 
daily for forty days, no appreciable change in the number 
of the corpuscles takes place. Pisemski, who poisoned 
his animals by smaller amounts, both dogs and rabbits, 
reached similar conclusions, but states that, ultimately, 
there ma}- be a decrease in the number of these bodies, 
owing rather to the exhaustion of the animal than the 
direct influence of the drug. 

Tissue Waste, or Bodily Metabolism. — Although 
fever depends primarily upon the action of disordered 
nervous protoplasm, it secondarily rests largely upon 
the destruction and repair of the tissues of the body. 
If the fever is high, the tissues are more rapidly de- 
stroyed, and as a result the urine, as the chief carrier 
of the excretions, is laden with the increased amount of 
nitrogenous and other matters thrown off. 

1 Bartholow, Therapeutics, 1887, p. 381. 

2 Lyon Medicale, March 3, 1889. 

3 St. Petersburg Inaug. Dissert., 1887, p. 48. 



24 Fever: its: Pathology and Treatment. 

Closely following the calorimetrical studies which 
have been made, a number of observers have studied the 
effect of antipyrin upon the destruction of tissue in 
fever, with results which, considering the complexity of 
the subject and the constant variation in the body, are 
of unusual similarity. By far the most thorough and 
complete study of this subject that we have yet seen is 
that of Robin, 1 who has confined his attention solely to 
the kidneys and their secretion when antipyrin is used. 
Taking six healthy men, he found that when as much as 
from 30 to 45 grains of antipyrin were given there fol- 
lowed a decrease in the quantity of urine amounting to 
20 or 40 per cent., and that in one or two instances this 
decrease was still more marked. 

This result is also confirmed by Jabubowitsch 2 in 
the case of children, and b}^ Dujardin-Beaumetz. 3 The 
urea was decreased in amount, whether the subject ex- 
perimented upon was well or sick ; while the uric acid 
was increased in healthy persons, but remained constant 
in amount in the sick, or else varied slightly. 

The chlorides were diminished in most cases, but in 
one instance they were unaffected. 

Wickowski has also noted a considerable diminution 
in the amount of the chlorides in the urine under the 
influence of antip3^rin. Robin has found that in chronic 
diseases the diminution of the quantity of urine under 
doses of antipyrin w T as more marked than in acute 
diseases, and that the decrease was greatest in those 
diseases where nutrition was most affected. 

The writer w r ould not be doing justice to this subject, 
however, did he not point out one or two points in the 

1 Gazette Me'd. de 1' Algerie, Jan. 15, 1888. 

2 Jahrbuch fur Kinderheilkunde, 1885, Bd. xxiii, No. 4. 

3 Therapeutic Gazette, 1885, p. 580. 



Antipyrin : Experimental Evidence. 25 

method of Robin which, while they do not of necessity 
involve inaccuracy in result, to a certain extent endanger 
the worth of his conclusions. Estimates of the quantity 
of solids excreted by the kidneys must necessarily be 
surrounded by so many conditions productive of error 
that all experiments should be most carefully guarded 
against fallacies. Particularly is this the case where the 
influence of one or two closes of a drug is to be con- 
sidered, for it is perfectly possible that the medicament 
may so influence the renal structure as to cause a tem- 
porary diminution of excretion, which does not neces- 
sarily indicate an actual decrease in tissue waste. Renal 
torpidity may show itself by decreased elimination, 
which passes away in the course of a short period, to be 
followed by the elimination not only of the tissue waste 
of the time being, but that of the period during which 
the kidney remained inactive. It is this point which 
Robin has overlooked, and in consequence of which his 
research is decreased in value. 

The communication of Robin has, however, been 
supported by the experiments of Umbach, 1 who, having 
made a series of studies on himself in health under large 
doses of antipyrin, finds that, while the quantity of his 
urine was not altered, there was nevertheless a very 
notable decrease in the elimination of urea, and asserts 
that antipyrin checks tissue metamorphosis very greatly. 
The uric acid was not altered in quantity. His method 
consisted in estimating the amount of sulphuric acid 
and uric acid, and the total quantity of nitrogen ex- 
creted normally and under the influence of the drug. 

The records of Riess 2 and of Muller, 3 from experi- 

1 Archiv fur Exper. Pharmacol, und Pathol., xxi, Nos. 2 and 3. 
3 Archiv fiir Exper. Pharmacol, und Path., 1886, xxi. 
* Jahresbericht fiir Thier-chemie, xiv. 
2 B 



26 Fever : its Pathology and Treatment. 

mentation on the patients under their care, also confirm 
the conclusions of Robin and Umbach. Riess selected 
typhoid patients in the height of their fever, and, after 
regulating their diet most carefully and preventing the 
appearance of all causes calculated to disturb the elimi- 
nation of tissue waste, measured with Teutonic accuracy 
the nitrogenous excretion during nine consecutive days, 
which period was separated into three divisions. During 
the first three da} T s the fever was allowed to run its 
course untreated, for the next three da} r s it was kept 
down b} r ordinary amounts of ant i pyrin, and during the 
last three days the fever was once more allowed to exist 
without treatment. It is unnecessary for the writer to 
enter into greater detail as to the methods emplo} T ed, 
as they seem beyond criticism. Suffice it to state that 
Reiss found, in the days during which anti pyrin was 
given, that the quantity of nitrogenous matter elimi- 
nated was decreased from 15 to 30 per cent., as compared 
with the days during which no drug was exhibited. 

In the experiments of Miiller, made upon a case 
under his care, it was found that the nitrogenous 
matters in the urine were decreased 28 per cent, when 
the fever was controlled by antipyrin,as compared with 
those given off on alternating da} T s when no antipyrin 
was employed. Engel, 1 under like circumstances, has 
noted a decrease amounting to from 16 to 25 per cent. 
The same results have been reached by Wiczkowski, 2 
Girard, 3 and Lahousse. 4 The last observer carried out 
his studies on himself, and used the methods of Kjeldahl 
in the estimation of the salts and other urinary con- 

1 Beitrage aus d. Wurzburger Klinic, Bd. ii, p. 146. 

2 Quoted by Umbach. 

3 Annals de la Soc. de Med. d' Anvers Aout, 1887, p. 231. 

4 Revue Me'd. de la Suisse Romande, vii, p. 642, 1887. 



Antipyrin : Experimental Evidence, 27 

stituents, or, in other words, employed methods identi- 
cal with those followed by Umbach. 

In children, Jacubowitsch 1 asserts that the elimina- 
tion of urea is greatly decreased, and condemns the use 
of antipyrin for this reason, and in a series of cases 
Walter 2 noted similar results after doses of 45 to 100 
grains a day. 

The evidence contradictory to the statements and 
researches of all the investigators just named is com- 
paratively slight, and, while worthy of notice, probably 
depends upon some fallacy for its existence. Thus, we 
find that Crolas and Hugounenq 3 state that the quantity 
of urine excreted is not diminished, and that the quantity 
of urea is increased. They also assert that the phos- 
phoric acid does not undergo alteration in respect to its 
quantity, 

Pavlinow 4 also states that the amount of the urine is 
unchanged, — a statement indorsed by Kumagawa, 5 who, 
after experiments on dogs with doses of large size, finds 
neither a decrease nor increase in the total nitrogenous 
elimination per day. This last investigator did find, how- 
ever, a great increase in the uric acid, which amounted 
to more than double the normal quantity. 

Devraux-Armand 6 found a decided increase in the 
elimination of urea in his own case under the use of 
45 grains a day of antipyrin. 

In view of the very great number of persons who 
find a decrease in nitrogenous change after the use of 
antipyrin, as compared with those who do not, and con- 
sidering the care exercised by many of the former class 

1 Jahrbuch f iir Kinderlieilkunde, 1885, Bd. xxiii, No. 4. 

2 Vratsch, No. 30, 1885. 3 Lyon Medicale, March 3, 1889. 
4 Meditzinskoie Obozrenie, f asc. xii, 1885, p. 1203. 

6 London Medical Recorder, Oct. 20, 1888. 
6 These de Nancy, 1885. 



28 Fever : its Pathology and Treatment. 

in their studies, it would seem that we have a right to 
conclude that antipyrin does decrease nitrogenous 
elimination, as a general rule. 

Having decided that antipyrin decreases nitrogenous 
changes, we are at once brought face to face with the 
question as to whether this decrease is primary or 
secondary in its causation, or, in other words, is this 
the result of a direct influence of antipyrin, or is it 
simply brought about by the decrease in fever and con- 
sequent decrease in tissue waste. Umbach has, fortu- 
nately, not overlooked this question, and by making two 
series of experiments, one of fourteen clays and one of 
six days, he found, in both series, that the nitrogen 
eliminated on antipyrin days, in himself, a healthy man, 
was 10 per cent, less than on normal days. That this 
was due to decreased waste, not to retention, is proved 
by the fact that on the days following the use of the 
drug the nitrogen gained its normal level, and no more. 
It seems, therefore, that the decrease is a primary one, 
although in fever there can be no doubt that it is also 
secondary. 

In respect to the changes that take place in the ex- 
pired air, and which give evidence of tissue metamor- 
phosis in the body, we have for study the papers of 
several investigators. Livierato 1 has found a diminu- 
tion in the amount of the carbonic-acid gas, and Henri- 
jean 2 has noted in fevered animals a notable decrease in 
the absorption of oxygen when antipyrin is used. 

In the normal rabbit, our own countrymen, Chit- 
tenden and Cummins, 3 have been unable to note any 
change in the elimination of carbonic acid under large 

1 Rivista Clinica di Bologna, 1885. 

2 Travaux du laboratoire de Leon Fredericq, t. i, 1885-86, pp. 288, 289. 

3 Physiol. Lab., Yale, Sheffield School, vol. ii. 



Antipyrin: Experimental Evidence. 29 

or small doses, which is remarkable, in view of the fact 
that if very large amounts are given the haemoglobin 
must be so altered as to produce some such change, 
without doubt. 

Very closely allied to these questions is the research 
of Lepine, 1 wiio concludes that antipyrin opposes the 
glycogenic function of the liver, and so, at least in 
part, diminishes the production of heat by an influence 
exercised on the hepatic cells. 

Nervous System. — When very large, massive doses 
of antipyrin (4 or 5 drachms) are injected intra-venously 
into one of the lower animals, the animal immediately 
becomes relaxed and weak, and in a moment falls to the 
ground, totally unable to move. Respiration becomes 
more and more feeble and finally ceases in death. This 
result, obtained by the writer, has been confirmed, in the 
frog, by Coppola, 2 Demme, 3 and Arduin, 4 and there can 
be no doubt of its correctness. Under these circum- 
stances there is, of course, total loss of reflex activity. 
Blumenau has also noted a decrease in the irritability of 
the cerebral cortex of the dog after massive doses were 
used. 

When smaller but poisonous doses of antipyrin are 
given to the dog and rabbit, or to the cat, convulsions 
of a tetanic type rapidly come on. The spasms are also 
somewhat clonic, or may be at one moment tonic and 
the next clonic. They are exceedingly severe, the animal 
being thrown hither and thither by their intensity. Con- 
sciousness seems to be preserved, though it has been 
proved that it is the brain which is largely acted upon 
by the drug under these circumstances, since section of 

1 Lyon Medicale, iii, 1889, and Arch, de Med., exp., Jan., 1889. 

2 Robert's Jahresbericht, 1885, p. 314. 

3 Fortschritte der Medio in., 1885, ii., 657. 4 These de Paris, 1885. 



30 Fever: its Pathology and Treatment. 

the cord stops the disturbance in the lower half of the 
body. 

The following experiment performed by the writer 
shows this : — 

Dog ; weight, 2YJ lbs. Black bull-dog, full grown. 

4.05. Gave 160 grains of antipyrin by the jugular vein 

in about one ounce of pure water. 

4.06. Seems restless. 

4.07. Has just had a slight convulsion. 

4.08. Another convulsion. 

4.09. Convulsion after convulsion ; now tonic, now 

clonic ; is thrown from side to side. Twists 
and squirms and rolls over and over in the 
spasms. 
4.12. Section of spinal cord at the fourth dorsal ver- 
tebra. 
4.20. Fore-legs still convulsed, with head and neck; 

hind-legs quiet. 
4.25. Killed by chloroform. 

These results are confirmed by the earlier ones of 
Wood, 1 Reichert,and the writer, and by Coppola, Leon- 
Arduin,Demme, Blumenau, 2 and Pavlinow. 3 They also 
receive further confirmation through the experiments 
of Chouppe, 4 who has found that the convulsions of 
antipyrin do not produce cramp asphyxia, as do the con- 
vulsions which arise purely from the spinal cord. 

As one would readily suppose, from the general 
nervous symptoms just detailed, there are two stages, or 
rather states, of reflex activity. If the dose has been 
excessively large reflex activity is lost at once, but if it 

1 Therapeutic Gazette, 1886. 

2 Wjestnik psichiatrii i nevropatologii, 1838, v-vi. See also St. 
Petersburger Med. Wochenschrift, No. 52, 1887. 

3 Meditzinskoie Obozrenie, fasc. xii, 1885, p. 1203. 

4 La Semaine Medicale, July, 1887. 



Antipyrin : Experimental Evidence. 31 

be only sufficient to cause convulsions the reflexes are 
not only preserved, but increased. Thus, Blumenau 
states that he has found, in the dog, cat, and frog, an 
increased reflex excitability to tactile and electrical 
stimuli, but no change in response to chemical irritation, 
when a convulsing dose is given, and he is confirmed by 
all the observers who studied the spinal action of the 
remedy. 

Besides the state of reflex activity from poisonous 
doses, we have undoubtedly a state of decreased reflex 
action produced by medicinal doses of the drug. This de- 
crease is not only seen clinically, but has been proved 
to exist by Germain-See and Gley, 1 as well as Lepine 2 
and the writer. The first of these investigators saw 
in dogs a marked decrease in reflexes, to such an ex- 
tent that galvanization of the sciatic nerve caused only 
a feeble response, and found that this was due to de- 
pression of the sensory nerves and the receptive side of 
the cord. Lepine has found that if the nerve in one leg 
be protected from the poison by ligature, it will respond 
much more readily to the stimuli than will that of the 
unprotected limb. From these researches it is evident 
that ample cause for decreased reflex action is present. 

Practically, Chouppe has found that antipyrin tends 
to prevent strychnine convulsions by this depressant 
influence. 

Respiration. — According to the writer's studies, and 
those of Batten and Bokenham, 3 death from antip} T rin, 
when given in lethal doses to one of the lower animals, 
results from failure of the respirator}' centre. In ordi- 
nal doses no change in respiration occurs, but, accord- 
ing to Pavlinow, 4 large doses make it more rapid. This 

1 LTUnion Meelicale. April 26, 1887. 2 Lyon Medicale, liii. 

8 Lancet, June 1, 1889. 4 Loc. cit. 



32 Fever : its Pathology and Treatments 

assertion is supported by the writer's observations, and 
is, in his estimation, correct. 

Elimination. — The elimination of anti pyrin goes on 
very rapidly, indeed, and begins almost immediately 
after its ingestion. Thus, Maragliano 1 states that it 
appears in the urine three hours after its ingestion. At 
the fourth hour the elimination is at its height, and 
continues for twenty-four or thirty-six hours. Anti- 
pyrin is also eliminated by the salivary glands, accord- 
ing to Pavlinow. Pavay 2 states that anti pyrin appears 
in the urine in one or two hours, and that the addition 
to this liquid of chloride of iron causes the development 
of a red-brown color. 

Toxic Effects from Prolonged Use of Antipyrin. — 
So far as the writer is aware, no case of severe chronic 
poisoning has ever been reported as the result of anti- 
pyrin, but it is interesting to know what changes occur 
under such circumstances in the lower animals. 

By far the most thorough research on this subject is 
that of Pisemski, carried out in the laboratory of Ivan- 
ovski upon healthy adult rabbits and dogs. It was 
found that when the drug was introduced under the 
skin of a rabbit in the daily dose of 7^ grains, death 
ensued on from the sixteenth to the thirty-first day ; or, 
if the dose amounted to 15 grains daily, death occurred 
in a few da}^s. If the dose amounted to 23 grains, 
death occurred one and one-half hours after the injec- 
tion. In dogs, if the daily dose was 15 grains, the ani- 
mals died on the fifteenth and twentieth day, or if it 
amounted to 45 grains daily, death came on the succeed- 
ing day. 

The chief changes noted by Pisemski at the autopsy 

1 Robert's Jahresbericht, p. 313, 1885. 

2 Wien. Med. Wochenschrift, 1886, No. 8. 



Antipyrin : Experimental Evidence, 33 

were intense engorgement of the brain and meninges, 
with a serous exudate into the cerebral ventricles. 

The lungs were highly congested and had a bright- 
red hue. The spleen was small and shriveled, while the 
kidneys were congested and slightly inflamed. The liver 
was not much affected and the red blood-corpuscles 
were greatly decreased in number. 

The lethal dose of antipyrin for the rabbit is said by 
Dujardin-Beaumetz to be 22 grains to every two pounds 
of the animal's weight. 

Antiseptic Action. — According to Brouardel, 1 anti- 
P3 T rin exercises a very distinct antiseptic influence. On 
fermentation, such as seen in beer, it acts quite power- 
fully, delaying or preventing it. The quantity of anti- 
pyrin required was found to be below 1 per cent, to 
delay it and 5 per cent, to prevent it. 

On the germination of seeds the drug also exercised 
a very marked action, delaying this process many 
hours. 

It was also found that, added to blood, it prevented 
putrefaction if present in the amount of 10 per cent. 

Coppola 2 has also noticed that antipyrin in 3-per-cent. 
solutions prevents alcoholic fermentation, as well as the 
action, of malt diastase. 

On the alcoholic fermentation of wine a very decided 
inhibitory effect was produced. 

Conclusions as to Physiological Action of Anti- 
pyrin. — 1. Antipyrin generally lowers normal bodily 
temperature to some extent. 

2. It lowers, to a very remarkable degree, febrile 
temperatures. 

3. The lowering of normal bodily heat depends 

1 La Semaine Medicale, Dec. 21, 1887. 
9 Jahresbericht fur Thierchemie, 1885, p. 98. 
2* 



34 Fever: its Pathology and Treatment. 

upon a lessened production of heat, followed by a de- 
creased dissipation. 

4. The same process takes place in the reduction of 
fever by this drug. 

5. The effect upon the circulation produced by anti- 
pyrin in the normal and febrile animal is virtually nil. 

6. Antip3 T rin changes the haemoglobin of the blood 
into methsemoglobin only when it is given in excessive 
quantity. In ordinary amount it has no influence on 
this tissue. 

7. Under its influence the quantity of urine is 
decreased and the urea and other evidences of tissue 
waste are also diminished. 

8. AntipjTin diminishes reflex activity by depress- 
ing the sensory and motor tract of the cord and the 
motor and sensory nerves, the latter being most affected. 

9. On normal respiratory movement its influence 
amounts to almost nothing in ordinary amount. In 
poisonous dose it causes death by respiratory failure. 

10. It is eliminated very rapidly from the body by 
the kidneys. 

11. Given for a great length of time in large amount, 
it is distinctly poisonous. 

Clinical Evidence. 

Turning from the experimental evidence which we 
possess in regard to the influence of antipyrin upon the 
animal economy, let us consider its use by the bedside, 
taking up seriatim the purposes for which it is employed. 
At the present time little doubt can exist but that it is 
the most reliable antipyretic substance that we have, if 
the fact be borne in mind that it also possesses very 
little power for producing serious liarm to the patient, 
even if idiosyncrasy to it exists. 



Antipyrin : Clinical Evidence. 35 

Large as is the literature of the experimental and 
scientific side of this subject, it is but a "drop in the 
bucket," as compared to the enormous mass of material 
which has been placed before us by almost every phy- 
sician in the civilized world. For years the medical 
journals of every language have teemed with clinical 
reports, and no sooner has the value of the drug in one 
malady been well discussed than a host of clinicians test 
it and write of its use in another. 

Born to the profession of medicine at a time when 
the medical heart was yearning for some elegant way of 
reducing the fever heat, which Liebermeister had so 
ably proved to be deleterious to the patient's welfare in 
prolonged fevers, antipyrin was at once seized upon and 
used by every practitioner with feverish haste. So rapid 
was its wave of progress that the medical student who 
had just graduated in the spring, without knowledge of 
the drug, found it in wide-spread use almost before he 
could find a spot in which to begin the practice of his 
profession. For this reason an attempt to embody the 
literature of antipyrin in &ny essay would be absurd ; 
even if room for all the clinical reports could be found, 
they would be but dry and uninteresting reading, and it 
is the author's duty to gather up the good grain from 
the tares rather than to bring before the reader for his 
examination the entire crop of communications as a 
garnered harvest. 

The writer of this essay, therefore, will confine him- 
self solely to those points which have been made by 
authors whose observations are most worthy of credence, 
and to the results obtained by himself in the use of anti- 
pyrin in the wards of St. Agnes Hospital and elsewhere. 

In order that the subject may be the more clearly 
understood and considered, it is, perhaps, best to divide 



36 Fever : its Pathology and Treatment. 

it into four parts, namely, the general influence of 
anti pyrin, its influence and use in fever, its power 
over the nervous system, and its effects upon malarial 
poisoning. 

General Influences. — When antipyrin is given in 
the dose of 10 to 20 grains to a healthy man, it produces 
either no symptoms at all or else a more or less well- 
marked ringing in the ears, accompanied with a sensa- 
tion of fullness of the head. The bodily temperature 
varies under its influence but the fraction of a degree, 
and no change at all may occur. 

If as much as 60 grains are taken at one dose, nausea, 
followed by vomiting, may at once come on, while the 
slight cerebral symptoms already named may become 
very violent. Generally, these symptoms are of short 
duration, but they may last for several days in persons 
who are susceptible to the drug. Very rarely untoward 
effects assert themselves in susceptible persons, but 
when they do occur they are as various in their forms 
as are the persons who have the symptoms. Aside from 
the results of poisonous doses, a large number of cases 
present slight cyanosis or duskiness of the hands and 
face about the nose and lips. The fingers may be cold 
and clammy , and the feet are often very cold. Sweating 
is a very common symptom of an untoward influence, 
and prickling or tingling of the skin is not uncommonly 
seen. 

By far the largest number of these cases, however, 
suffer from disorders associated with the skin. Ery- 
thematous patches can be seen everywhere, more par- 
ticularly on the hands and feet and about the face and 
arms, or on the chest. In some instances pemphigus- 
like spots appear, and even large bullae have been noted 
as present. 



Antipyrin: Clinical Evidence. 37 

If the reader will glance at the tables following this 
page, he will see how the symptoms vary, and how dif- 
ficult it is to discover more than a few points common 
to all cases. Notwithstanding this fact, however, it is 
of some importance to study the results reached by an 
analysis of the hundred and odd cases here collected. 
At the very first glance, it is readily seen that the num- 
ber of instances where untoward effects were present in 
females is largely in excess of those instances in which 
they occurred in males ; and it is also worthy of note 
that the prevailing age was decidedly that of full adult 
life, namely, from 30 to 40 years, both in males and 
females, as may be seen from the following tables : — 

Males. 
Age, 1 to 10 years, 4 cases. 





Females, 




Vge 


i, ltolO; 


years, 


6 cases. 


« 


10 to 20 


i i 


12 " 


ti 


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u 


8 " 


u 


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a 


15 " 


it 


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a 


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a 


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a 


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a 


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a 


5 


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a 


5 


a 


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it 


4 


a 


40 to 50 


tt 


3 


a 


50 to 60 


it 


1 


case, 


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tt 


1 


a 



Passing on, we find that the dose which caused 
untoward effects was generally a moderate one, and that 
it was from 10 to 15 grains in most instances, and next 
most frequently from 5 to 10 grains. It is also to be 
seen, on analysis, that this proportion holds good in 
males as well as females, although, of course, to a much 
less degree. A glance at the next column of the tables, 
that on the time of onset, will show that this species of 
information may be divided into two sets. One of these 
is when the drug was taken for a length of time before 
bad effects were noted ; the other, when the evil effects 
came from a single or double dose. It will also be seen 
that, when single or double doses were the cause of the 



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54 Fever: its Pathology and Treatment. 

trouble, the onset was, in a very large percentage of the 
cases, immediate. Where the dose of the drug had 
been frequently repeated, it will be noted that the onset 
was also sudden rather than gradual. As a rule, the 
duration of the s} T mptoms did not exceed three hours, 
and three days is the longest time mentioned for the 
continuance of the bad effects ; while one hour was often 
the length of time during which serious effects were 
felt. 

As yet, however, we have not come to the part of 
the subject which, after all, is the most important to the 
practitioner of medicine and to the patient also, and is, 
in consequence, the most interesting part of the question 
before us. In the hundred and odd cases here gathered 
in which the drug produced evil results, only 6 proved 
fatal, and in these there was ample cause for death aside 
from any effect of the drug. In one case puerperal fever 
was present in an aggravated form, in another fatty 
kidneys were found at the autops}^, while in the third 
and fourth t} T phoid fever w 7 as present. In the remain- 
ing 2 cases the reporters state that death was not 
certainly due to the drug, and perhaps would have oc- 
curred with equal rapidity if no antipyrin had been 
given. We can rest assured, therefore, in ordinary cases 
of disease occurring in patients who exhibit untoward 
effects of antipyrin, that, even though the symptoms be 
most alarming, they so rarely end in death as to enable 
us to rid ourselves of alarm and quiet the fears of the 
patient's friends. 

A very interesting question in relation to the un- 
toward effects of antip3 T rin is the disease in which they 
most frequently assert themselves. On examining these 
statistics, we find that it is in typhoid fever, in which 
the system is ever at a point at which it is susceptible 



Antipyrin : Clinical Evidence. 



55 



of external influence, that the sj^mptoms unwished for 
have most frequently appeared. This may be partly 
due to the fact that the drug has been given more largely 
in this disease than in any other. 
The record stands thus : — 



Typhoid fever, 


42 cases. 


Puerperal fever, . 


. 1 case. 


Articular rheumatism, 


7 " 


Sciatica, 


. 4 cases. 


Chronic rheumatism, . 


2 " 


"Fever," . 


. 2 " 


Migraine, 


5 " 


Thermic fever, 


. 1 case. 


" Nervous headache," 


5 " 


Not stated, . 


. 19 cases. 


"Pain," 


1 case. 


Neuralgia, . 


. none. 


Phthisis, 


5 cases. 


Pneumonia, . 


. 4 cases. 


Dysmenorrhoea, . 


1 case. 


Chorea, 


. 5 " 


Typhus fever, 


2 cases. 


Rheumatoid arthritis, 


. 1 case. 


Heart disease, 


1 case. 


Gout, . 


. 1 " 


Asthma, 


1 " 







Unfortunately, owing to the carelessness of the origi- 
nal reporters, information, in a sufficient number of 
cases to be of any value, cannot be obtained as to the 
occupations and temperaments of the sufferers. 

It is impossible to give in detail all the references to 
the use of antipyrin in the diseases in which it has been 
employed. One can but give the gist of the papers 
which have made the epoch-markings in its therapeutic 
progress, and thus embody in a short space the opinions 
of those best qualified to speak of the matter in hand. 

A very exhaustive paper, one of the best which have 
been published, is that of Reihlen, 1 of Nuremberg, em- 
bodying the results of a careful study of no less than 
89 cases, of which 29 were suffering from typhoid fever, 
16 from croupous pneumonia, 11 from facial erysipelas, 
10 from acute articular rheumatism, 7 from pulmonary 
phthisis, and the remainder from various diseases, such 
as malaria and similar affections. In all of these 89 



1 Deutsche Arch, fur klin. Medicin., April 22, 1886. 



56 Fever : its Pathology and Treatment. 

cases antipyrin never failed to lower the fever present 
within the first hour, and on no occasion was the fall so 
slight as to be useless from a therapeutic point of view. 
Aside from the fact that the degree of hyperpyrexia, 
rate of absorption, and dose are all determining factors 
in the rapidity and extent of its effects, the use of anti- 
pyrin is governed, according to Reihlen, by the age, 
sex, and constitution of the patient, by the method of 
administration, and by the other measures adopted for 
the relief of the patient. It was also found that the 
mode of giving the daily amount and the nature and 
stage of the disease bad much to do with the fall. The 
weaker the patient, the more powerful is the drug for 
reducing fever. A very important point which Reihlen 
calls attention to is the fact that if the action of anti- 
pyrin becomes associated with a spontaneous fall of 
temperature, as at the crisis of a disease, the resulting 
reduction of bodily heat is colossal, and collapse often 
ensues. Unless the amount of antipyrin reaches 25 or 
30 grains, Reihlen thinks the drug lacks the power of 
lowering the temperature before the disease reaches its 
pyrexial acme. 

A very interesting assertion is made by Reihlen, 
namely, that tuberculous diseases, or complications, 
render the antipyretic action of antipyrin very powerful, 
and so frequently did this observer note this that he 
suspects tubercular change in every case of fever which 
is peculiarly susceptible to the drug. Contraiy to the 
assertions of Demme, Reihlen thinks that hourly doses 
are much more efficacious than single daily administra- 
tions, and he gives as much as 100 grains in divided 
doses whenever necessary. Reihlen makes one assertion, 
however, from which we must distinctly differ, namely, 
that antipyrin affects the heart as constantly as the 



Antipyrin: Clinical Evidence. 57 

temperature, — an assertion which is untrue, in that the 
drug does not do this directly, but indirectly, — a subject 
of which the writer has already spoken in the general 
consideration of antipyretics in the preceding pages of 
this essay. This is proved by Reihlen himself, who 
states that the fall of pulse is pari passu with the fall of 
temperature, and that the rise of pulse-rate and tempera- 
ture also go hand in hand. Again, lie states that in the 
afebrile cases, where antipyrin was given, the pulse re- 
mained unaltered, — a clinical proof of the truth of this 
assertion. Although von Noorden, 1 Demme, 2 and Calm 3 
also noted changes identical with those named by 
Reihlen, there can be no doubt that they were dependent 
on the fever, and not on the drug. 

On the general systemic condition under antipyrin 
Penzoldt 4 gives us verj- positive opinions. He states 
that in children the general condition is greatly improved 
by the use of the drug. They appear to be more lively, 
sleep better, and cough less. This was the conclusion 
reached by those physicians who gave the drug during 
the great measles epidemic of 1884, in Nuremburg. 

Other observers are not, however, universally in 
accord with these clinicians. Thus, May found only 
three cases, out of a large number, which were improved 
by antipyrin, and Alexander 6 saw but one such instance. 
More than this, Ernst, 6 ' of Zurich, speaking of the great 
epidemic of typhoid fever in 1884, states that u it is 
once more proven how little is sometimes accomplished 
by a mere apyresis, delirium and other symptoms taking 

1 Berliner klin Wochenschrift, 1884, No. 32. 

2 Fortschritte der Medicin., Nos. 20 and 21, 1886. 

3 Berliner klin. Wochenschrift, 1886. 
*76zU, 1884, No. 30. 

6 Breslauer Arztl. Zeitschrif t, 1884, No. 11. 
6 Bulletin Gen. de Therapeutique, Oct. 4, 1884. 
3* 



58 Fever: its Pathology and Treatment. 

their course, as usual." Reihlen is also in accord with 
Ernst in this, and these assertions are, therefore, inter- 
estingty opposed to those of Liebermeister, 1 who regards 
the increase of temperature not only as dangerous, but 
also as the direct cause of its chief characteristics. 

A very interesting clinical comparison of antipyretic 
power has been made by Pavay 2 upon a febrile patient 
suffering from phthisis. Using quinine, salicylate of 
sodium, and antipyrin, he found that the effects were 
identical if of quinine 15 to 22 grains, of antipyrin 37 
grains, and of salicylate of sodium 45 grains were used. 

In Ziemssen's Archiv fur klinische Medicin, Sara 
Welt has recorded the results of the use of antipyrin in 
122 cases, of whom 62 were males and 60 females. Of this 
number 88 suffered from enteric fever. 

She found that doses of 30 grains secured complete 
effects in 72 cases 490 times, while a dose of 120 grains 
caused a complete apyrexia on one occasion at once, and 
150 grains acted similarly in another patient, — a result 
not to be wondered at save that death did not occur as 
a result of the avalanche of drug. 

In France, Laure 3 has tried the drug in the children's 
wards of the Gharite de Lyon, and he concludes that 
antipyrin is far superior to quinine in all the febrile 
maladies of childhood, save malaria, and that it is par- 
ticularly valuable in children. This opinion is also con- 
firmed by Moncorvo, 4 of Brazil, but is vehemently 
opposed by Jacubowitsch, who asserts that, by reason 
of the decrease in urinary flow, the drug is dangerous 
in children. 



1 Deutsche Arch, fur klin. Med , vol. iii, 1867. 

2 Wiener Medlcin Wochenschrift, 1886, No. 8. 

8 Revue Mensuelle des Malades de FEnfauce, Feb., 1886. 
4 Berliner klin. Wochenschrift, April, 1887. 



Antipyrin : Clinical Evidence. 59 

One of the best studies as to the value of antipyrin 
in children's ailments has been recorded by Argutinski, 1 
who has used it in croupous pneumonia, the patients' 
ages being from 4 to 8 years. The drug was given in 
doses of from T to 15 grains every hour for two or three 
doses. 

It was found that the fall of temperature usually 
began after the first dose, and fell rapidly during the 
first three hours, after which time it continued falling or 
remained stationary for twelve to eighteen hours more, 
and, if very large doses were used, the apyrexia lasted 
for forty-eight hours. 

In 4 cases out of 5 no rise occurred in the tempera- 
ture after the primary fall. The heart and circulation 
remained unaffected, except that the pulse became a 
little slower with the decrease of the fever. No exhaus- 
tion was produced by the drug, and the condition of the 
patients became more cheerful and bright. 

In the Prager Medicinische Wochenschrift 2 Pri- 
bram published one of the earliest clinical reports that 
we possess of the value of antipyrin. From these 
studies he concluded that it acts when quinine fails, 
that it is as efficacious in acute rheumatism as salic} T lic 
acid, and that in phthisis it tends to prevent loss of 
bodily weight. In Schmidt's JaJwbucher 3 may be 
found several papers of a similar character. 4 

It is worthy of note that Ernst 5 was one of the first 



1 Vratsch, Nos. 41-42, 1884. * Oct. 1, 15, 22, 1884 

3 Oct. 21, 1884, p. 127. 

4 The following is a list of the more important papers appearing at 
this time : Filehne, Zeitschrift fur klin. Med., viii, 1884. Guttmann, Ber- 
liner klin. Wochenschrift, No. 20, 1884. Alexander, Breslauer Arztl. Zeit- 
schrift, ii. Hofer, Wiener Med. Wochen., No. 47, 1884. Batak, Casopis 
ceskych lekarnv, Nos. 47-52, 1884. 

8 Bulletin Gen. de The'rapeutique, Oct. 30, 1884. 



60 Fever : its Pathology and Treatment. 

to notice the exanthematous rash which sometimes 
appears. 

The important statement of Steell, 1 made in 1885, 
that typhus fever fails to respond to aiitipyrin as favor- 
ably as does typhoid fever, has been found true by 
others and is worthy of attention. 

Antipyretic Influence. — Ever since Filehne 2 re- 
ceived from the hands of Ludwig Knorr, of Munich, the 
substance known as antipyrin, the drug has been used 
to check fever with almost certain results, and so gen- 
erally recognized is this power that the writer will not 
stop to give a long array of evidence as to its existence. 
He will rather attempt to point out the conditions and 
circumstances which call for its use and under which it 
will most probably act advantageously or disadvan- 
tageous^. 

The question of vital importance which at once 
comes forward for decision is as to whether a drug 
which lowers a fever in any way shortens the duration 
of those diseases which run a given course, as typhoid 
fever, pneumonia, or any one of the affections which end 
in crisis or lysis. 

While it is true that . antip\ T rin may be employed in 
any disease associated with high temperature, such as 
typhoid fever, pneumonia, or erysipelas, it must not be 
forgotten that but one object is gained by its use. Anti- 
pyrin, even though its influence may be most favorable 
in a given case, still accomplishes nothing in the way of 
cure. Antipyrin on\y governs the heat processes while 
the disease plows its wa\ r onward to recovery or death ; 
although it may, b}^ quieting restlessness due to the 
fever or to the nervous disorder produced by the dis- 

1 Med. Chronicle, 1884-85, p. 4&7. 

a Zeitshrift fur klin. Med. Berlin, 1884, vii., p. 641. 



Antipyrin: Clinical Evidence. 61 

ease, render the pathway to recovery more easy, but no 
shorter than if it were not employed. 

Many physicians have looked and still look upon 
antip3^retic treatment as curative in its effects, but 
nothing can be more distant from the truth. It should 
be distinctly understood and taught everywhere that 
these drugs belong to a peculiar class ; a class of drugs 
to which we gladly turn when told " to treat the S3^mp- 
toms as they arise ;" a class of drugs which are to be 
used solely for the relief of the symptoms of the disease, 
and not for the cure of the disease itself. 

Typhoid Fever and Fever of Typhoid Type. — In 
the early part of this essay the writer said so much con- 
cerning the time at which antipyretic treatment is to be 
resorted to that it is unnecessary to repeat it here. In 
his opinion, antipyrin should play a secondaiy role in 
the reduction of the pyrexia of the typhoid state, our 
main reliance being upon cold applications, and the anti- 
pyrin only being used as an adjuvant to help the cold 
bath or packing. Aside from the fact that he has found 
such an opinion to be well based upon good results in a 
large number of typhoid-fever cases, this belief seems 
to be founded upon perfectly good logical therapeutic 
reasoning. Even if antipyrin were perfectly innocuous, 
its constant use in fever would but give the already 
overstrained kidneys the task of its excretion, while the 
stomach, sufficiently disturbed by necessary medicine and 
illness, has enough to do without an additional load. 
Further than this, we know that the drug is not per- 
fectly harmless, and we also know that if it acts on the 
protoplasm of the body it must finally be given in larger 
and larger dose, lest it lose its power. This is not the 
case with the cold pack or application, which never loses 
its power through prolonged use. 



62 Fever : its Pathology and Treatment. 

The writer feels sure that antipyrin should be given 
in typhoid and other low fevers of a continued type only 
when the cold pack cannot be used, or at the end of the 
cold application to prevent the temperature from bound- 
ing upward after its depression. 

Further than this, the fever will sometimes resist all 
doses of antipyrin that we can give, or, at any rate, all 
that it is safe to give. No fever can resist the cold bath. 

In diseases of a more chronic type, more particularly 
those represented by phthisis, antipyrin is of doubtful 
value, owing to the increased sweating so apt to be pro- 
duced by the drug, and, unless the patient seems to be 
particularly robust, it should not be employed except in 
the smallest available doses. 

Sthenic Fevers. — The application of antipyrin to 
the febrile temperatures occurring in sthenic cases has 
an entirely different outlook and purpose than in the 
prolonged low fever of the adynamic type. There can 
be little doubt that in sudden, excessive outbursts of a 
febrile paroxysm in a child, without any acute disease 
underhying it, antipyrin is of great value, and there are 
also reasons for its employment in order to favor popu- 
lar prejudice. In America, at least, a physiean visiting 
a case of croupous pneumonia at its onset with a high 
fever would not be allowed to give the patient a cold 
bath, if the friends could prevent it, and must, in conse- 
quence, fall back upon antipyrin. 

Again, the fever of such cases is not prolonged 
enough to necessitate the use of antipyrin day after 
day, for weeks at a time, and there is, therefore, less 
danger of the body being injured by its influence. In 
scarlet fever its use should be most carefully watched, 
for the double reason that the kidneys are in danger, and 
that the disease, accompanied by fever, may last a long 



Antipyrin : Clinical Evidence. 63 

time. In pneumonia and erysipelas, in strong persons, 
antipyrin finds its true place. Lasting about a week in 
their febrile activity, these diseases are often accompa- 
nied by sudden hyperpyrexias, which must be overcome 
at once by a drug, and the fever is so apt to rise to a 
dangerous degree that some remedy has often to be left 
in the hands of the nurse, with instructions to use it if a 
hyperpyrexia should assert itself. 

In thermic fever, or the hyperpyrexia of sun-stroke 
the employment of antipyrin is often useless. The ex- 
cessive^ rapid upward dash of the temperature responds 
in no way to the drug, and there are cases on record in 
which its use has utterly failed of good result. Thus, 
in one case reported by Singer, 1 a man suffering from 
thermic fever with a temperature of 108.4° F. received 
50 grains of antipyrin hypodermically at 6 p.m. At T 
p.m. he received 10 grains more under the skin, and at 8 
p.m. 20 grains more. At 9.30 another 20 grains were 
used. In other words, 100 grains hypodermically in 
three and a half hours proved useless. 

That the drug may do good if the temperature is not 
excessive is proved by many observations, and an inter- 
esting clinical report on the successful use of antipyrin 
in the sun-stroke of children, which was -probably not 
true heat-stroke as we know it, has been published by 
Demme. 2 

It has been stated b} r some practitioners that anti- 
pyrin may produce serious cardiac weakness at the time 
the fall of temperature occurs, and these writers have 
pointed out that, though experimental studies show anti- 
pyrin in moderately large doses to be devoid of cardiac 
influence, clinical experience reaches opposite results. 

1 New York Medical Record, Dec. 25, 1886. 
9 Wiener Med. Presse, July 17, 1887. 



64 Fever : its Pathology and Treatment. 

This apparent contradiction between empiricism and 
science is, however, by no means real, as we will explain. 
The studies of Lauder Brunton and others, already 
quoted by the author of this essa} T , have abundantly 
proved that the application of heat, not only to the 
heart of the frog but to that of the mammal, renders its 
movements much more rapid, and, to a certain point, 
more powerful, provided that the heart has not been 
weakened by some prolonged exhausting condition and 
is in such a state that scarcely any measures can be 
resorted to for its restoration. In this we see an expla- 
nation, in part, of the high, bounding, but rapid pulse 
of sthenic febrile conditions. It is a law that every 
muscular fibre always experiences a condition of more 
or less depression after unusual exertion, and this is 
particularly the case whenever the stimulation causing 
the increased exertion is suddenly withdrawn. If, there- 
fore, the heart of a patient is stimulated by the height- 
ened temperature of a fever for a day or two and is 
alreadjr beginning to be tired out, it is evident that a 
large dose of anti pyrin may indirectly withdraw in a 
few minutes the only stimulus it has and produce a 
depressed condition of the cardiac muscle at a time when 
the general system, not depressed by the disease as jet, 
may be making as great calls for blood as before. The 
argument against this is, that if the fever by stimulating 
the heart will result in its exhaustion, the sooner the 
fever is reduced the better it is. This is partly true, and 
it is just between the points of too much drug and none 
at all that we must take our path, the idea being to 
relieve the fever slowly, not by one huge dose. This 
does not apply to those cases where the condition is one 
of rryperpyrexia and where the danger is immediate from 
involvement of the heart and hioher nervous centres. 



Antipyrin: Clinical Evidence. 65 

Malarial Disease. — In malarial disease antipyrin 
certainty exerts no antiperiodic influence, although it 
controls the febrile paroxysms to a very great extent ; 
yet, while this is the opinion of the majority of those 
who have used it, it cannot be said that every observer 
has reached similar conclusions. Thus, we find Potter * 
reporting cases where the results obtained were most 
satisfactory when large doses of antip} r rin, frequently 
repeated, were used. He obtained particularly good 
results from its use in the remittent type of malarial 
poisoning, and found it to succeed when the other 
measures usually employed had failed. 

One cannot help thinking that, in many of the cases 
where antipyrin has been reported as acting as an anti- 
periodic, it has simply lowered the fever, and so seemed 
to favorably affect the disease. Such an instance is 
recognized and mentioned in one of the recent German 
journals. 2 

Nervous Diseases, Particularly those Associated 
with Pain. — Almost as soon as it was discovered that 
antipyrin possessed antipyretic powers, it was known 
that it could also relieve pain, and, although this feature 
of its action was not fully recognized on all sides until 
the papers of Lepine 3 and See 4 were published, it had 
nevertheless been recorded previously by Alexander, 5 
Demme, 6 Demuth, 7 Masius, 8 Lenhartz, 9 Bernheim, 10 

1 Lancet, London, April 10, 1886. 
3 Deutsche Med. Zeitschrift, 1887. 

3 Centralblatt far die Gesammte Therap., Jan., 1887. 

4 L' Union Medicale, April 26, 1887. 

8 Centralblatt fur klin. Med., No. 33, 1884. 
6 Fortschritte der Medicin, No. 24, 1884. 
1 Aertzliches Intelligenzblatt, Dec, 1884. 
8 Bulletin de l'acad. Royale Med. de Belgique, No. 1, 1885. 
8 Chariten Annalen, Bd. x, 1885. 
10 Revue Me'dicale de l'Est, April 15, 1885. 
C 3 



66 Fever : its Pathology and Treatment. 

Neumann, 1 Blanchard, 2 Moncorvo, 3 Fraenkel, 4 and 
Clement. 5 All of these clinicians had, however, only 
found it useful in rheumatic and gouty pains, and it was 
rather supposed that the relief was due to an action on 
the disease than to an} r analgesic properties of the drug. 

The use of antipyrin for the relief of other pains 
than those just named, was undoubtedly first carried 
out by Khomiakoff and Livoff 6 in migraine, and by 
White 7 and Sprimont 8 in hemic rania, a virtually iden- 
tical neurosis. These results have been confirmed by 
Ogilvey, 9 Kingsbury, 10 Berdach, 11 Wright, 12 G-uardia, 13 
Suckling, 14 Pujardin-Beaumetz, 15 Ungar, 16 Martin, and 
an infinite number of others. 

By far the most important of these studies are those 
of Germain See, 17 and so similar are the results of the 
ever} r -da} T use of antipyrin at present to the observations 
of this writer that it is unnecessary to do more than give 
his conclusions, which sum up our knowledge, particu- 
larly if we include his second contribution 18 on the sub- 
ject. He found that the drug relieved in an extraordi- 
nary degree the agony of gout and of rheumatism and 



1 Berliner klin. "Wochenschrift, Sept. 14, 188-5. 

2 Revue Med. de la Suisse Rornande, May, 1886. 

3 Paris Thesis, 1886. 

4 Berliner Med. Gesellschaft, Oct. 18, 1886. 
6 Lyon Med., Aug. 29, 1886. 

6 Vratsch, No. 5, 1885, p. 867. 

7 New York Medical Record, Sept. 11, 1886. 

8 Med. Obozren, No. 23, 1886. 

9 British Med. Journal, Jan. 14, 1888. 10 Ibid., Dec. 24, 1887. 
11 Wiener Med. Wochenschrif t, March 10, 1888. 

13 Practice, Jan., 1888. 

13 Rivista de Ciencias Medicas Barcelona, Feb. 20, 1888. 

11 British Med. Journal, June 11, 1887. 

15 Therapeutic Gazette, Oct., 1887. 

16 Centralblatt fur die Gesamnite Therap., Jan., 1887. 

17 L' Union Med., April 26, 1887. 

18 Ibid., Sept. 10-13, 1887. 



Antipyrin : Clinical Evidence. 6t 

other forms of pain associated with diathetic states. 
More important than all, however, he recorded a large 
number of instances where the drug alleviated headache, 
facial neuralgia, and obstinate migraine with rapidity 
and completeness. He found antipyrin of value in the 
pains of neuritis and tabes dorsalis, and his assertion 
that it surpasses opium in giving relief in the crises of 
the latter disease has received confirmation the world 
over. 

In the contribution made some time later (loc. cit.), 
See recorded the relief obtained in cases of abdominal 
pain associated with visceral disturbances, such as renal 
and hepatic colic, colic of the gastro-intestinal type, and 
that associated with the uterus. He also praises the 
power of the drug in angina pectoris in all its forms, and 
the writer of this essay has also used it successfully in 
this disease. 

Almost synchronously with the appearance of this 
paper by See, one by Seifert, 1 of Wiirzburg, of a similar 
tj T pe was published, and the German writer not only 
supported the earlier author, but also recorded the value 
of antipyrin in chorea, — a report which has been highly 
indorsed by H. C. Wood 2 more recently in this country. 

Fraenkel, to test the correctness of the views of See, 
almost immediately took morphine away from his patients 
and substituted antipyrin in its stead, with the most 
encouraging results, and he further proved that the ac- 
tion of about 5 grains of antipyrin was equal to -^ 
grain of morphine. 

Even if it were possible, it would be out of place for 
the writer to give any further quotations from the litera- 
ture of this subject, and what has been said has been 

1 Centralblatt fur klin Med., No. 35, 1887. 

2 Therapeutics, Phila., 1888. 



68 Fever: its Pathology and Treatment. 

mentioned rather as an evidence of the diverse actions 
of the drug than with the idea of giving a thorough 
review of the general and wide-spread power of anti- 
pyrin for the relief of pain. 



ANTIFEBRIN. 
Experimental Evidence. 

Although brought to the physician as a remedy 
quite two years after its fellow, antipyrin, antifebrin 
has undergone an amount of study which only an epoch 
marked by a yearning after a good febrifuge could bring 
forth. Further than this, the clinical and physiological 
studies made upon it in many w r ays seem more to the 
point and more thorough than those on antip} r rin, per- 
haps because the examination of the effects of that drug 
had taught us what to look for. On the other hand, 
the partial insolubility of the drug renders physiological 
studies concerning it far more difficult of completion. 

Heat Functions. — Following out with antifebrin4he 
course already pursued with antipyrin, let us attempt 
to discover what its influence is upon the temperature 
of the normal animal. 

In the spring of 1887, the writer 1 and Evans 2 carried 
out a series of investigations as to the general effects of 
antifebrin, and paid especial attention to the question 
now before us. The writer found in rabbits, free to run 
about, that a very distinct fall, often exceeding 1° F.,in 
the normal bodily heat took place, and he also obtained 
a similar result with dogs attached to the manometer 
and in the calorimeter. His results were confirmed by 
Evans, who used rabbits in a calorimeter. On the other 
hand, Cahn and Hepp 3 did not find that antifebrin con- 
stantly produced a fall in the normal animal, but that 
it did do so in the majority of instances. The following 

1 Therapeutic Gazette, June, 1887. 3 Ibid. 

3 Centralblatt fur klin. Med., 1886, vii, p. 561. 

(69) 



70 



Fever : its Pathology and Treatment. 



experiments, made more recently by the writer, are of 
interest in this connection, as they tend to support the 
earlier statements already published : — 

Experiment No. 1. — Rabbit ; weight, 3 lbs. ; full 
grown; doe. 



1.13 

1.20 

1.30 

1.40 

1.50 

2. 

2.30 

3. 



Rectal temperature, 

Gave hypodermically 2 grains of antifebrin. 
Rectal temperature, 



102.1 

102.1 

102. 

101.4 

101.2 

101. 

101.2 

102. 



Experiment No. 2. — Rabbit ; weight, 2J lbs. ; 
grown ; buck. 

1.25 Rectal temperature, 103. 

1.28 Gave hypodermically into the side 2 grains 
of antifebrin. 

1.35 Rectal temperature, 102.9 

1.40 " " 103. 

1.50 " " 102.7 

2. " " 102.6 

2.10 " " 102.3 

2.20 " " 102.1 

2.30 " " 101.8 

2.40 " " 102.1 

2.50 " " 102.3 



full 



Experiment No. 3.- 
full-grown ; doe. 



-Rabbit ; weight, 2| lbs. ; black ; 



3.10. 
3.13. 
3.25. 
3.35. 
3.45. 
3.55. 
4.05. 
4.15. 



Rectal temperature, . 

Gave 2 grains of antifebrin as before, 

Rectal temperature, 



102.6 

102.7 
102.6 
102.3 
102.1 
101.7 
101.4 



Antifebrin : Experimental Evidence. 71 

That antifebrin lowers fever temperatures with great 
rapidity and thoroughness is so well attested by clinical 
observation as to make any examples of such an action 
unnecessary, for, if any is required, it can be found 
scattered everywhere through the literature of medicine 
for several years and is included in the clinical considera- f 
tion of the drug which follows this portion of this paper. 

It having been decided that antifebrin lowers normal 
heat, it remains to be discovered how this lowering takes 
place, and the experiments of the writer and Evans 
would appear to decide this point. Evans asserts that 
in 9 animals he found an increase in heat dissipation in 
7 cases, with a decrease in heat dissipation in the re- 
maining 2. In 5 of the 9 heat production was decreased 
and in 4 increased. In the studies made by the writer 
on 5 dogs he found production decreased in 4 cases and 
increased in 1. It would appear, therefore, that the 
fall is due to decreased heat production and increased 
heat dissipation, as a general rule. 

On the fevered animal, antifebrin acts by decreasing 
heat production and dissipation, according to the studies 
of both the writer and Evans; and, as the decrease in 
dissipation is not so great as is that of production, it is 
probable that it simply follows the lessened production, 
or, in other words, less heat being produced, less is 
eliminated. 

It has been stated by Wood that the researches of 
the writer and of Evans are here at fault, in that the 
temperature did not fall under the doses employed by | 
them. This is certainly untrue of some of the experi- 
ments of Evans and of some of those of the writer, as 
examination of their papers will show. Thus, in experi- 
ments No. 2, No. 3, and No. 5 of Evans, a fall of tempera- 
ture did occur, with the changes in heat mechanism 



72 Fever : its Pathology and Treatment. 

alreadj^ named ; and in those of the author, Nos. 17, 18, 
and 19 also showed a fall with the same changes in the 
heat functions. It would seem, therefore, that their con- 
clusions, as based on these experiments, are worthy of 
acceptance. 

Bokai 1 has also asserted that the power of anti- 
febrin in reducing temperature, when given in medicinal 
quantities, depends upon its power of lessening heat 
production. His basis for this is one which is partly 
hypothetical and partly founded on experimental proof, 
namely, that as the drug paralyzes the peripheral motor 
nerves, in poisonous doses, so does it also depress them 
when in medicinal amount, and thereby prevents heat 
changes in the muscles. 

This theory is one which it is impossible for the 
writer to consider, simply because we have no right to 
suppose that the muscles are our chief source of heat ; 
nor have we as } r et complete proof that paralysis of the 
motor nerves lowers heat production. Lastly, we are 
without evidence, even if these nerves contain trophic 
or heat fibres, that antifebrin paralyzes any fibres but 
those intimately associated with movement and not with 
nutrition. 

If a toxic dose is used, Bokai thinks that vascular 
dilatation is an important factor in the fall of tempera- 
ture and dissipation of heat. 

Circulation. — As the influence upon the circulation 
of any substance used as a drug must or ought to 
be known before it is generally employed, this portion 
of our study is most important. 

Dividing the circulatory effects into those changes 
produced by toxic and medicinal amounts, let us first 
consider the former. 

1 Deutsche Med. Wochenschrift, Oct. 20, 1887. 



Antifebrin: Experimental Evidence. T3 

When antifebrin is applied to the isolated frog's 
heart, Lepine 1 states that it beats more rapidly and 
strongly, but soon becomes weakened if the amount of 
the drug be large, the viscus finally ceasing to beat in 
wide diastole. The same result, so far as cardiac arrest 
is concerned, has been reached by Herczel, 2 experiment- 
ing on the rabbit, and Weill 3 has also noted that the 
heart of the frog, while at first stimulated, is ultimately 
depressed by large amounts. The writer has confirmed 
these results, and has also found that, when antifebrin in 
large amounts is injected into the jugular vein of a dog, 
it produces at once a fall in arterial pressure, with a 
diminution of the size of the pulse-waves, and all the 
general evidences of cardiac and circulatory depression, 
notwithstanding the fact that, as death occurs from respi- 
rator} 7 failure, asphyxia is present. (See tracing No. 1). 
The cause of this fall seems to be due to a direct depres- 
sing action on the heart, associated with failure of the 
vasomotor system, as asphyxia causes no rise in arterial 
pressure. 

Turning to a consideration of the influence of anti- 
febrin upon the circulatory system in ordinary medicinal 
amount, we find that it either has no influence, if the 
quantity of the drug be quite small, or else, if it be 
large enough to produce any change, we have a condition 
which does not seem to be dependent so much upon a 
dominant action of the drug as the state of the animal 
at that time. Thus, in the experiments detailed by 
Evans, 4 he found virtually no changes in pressure and 
pulse-rate in two experiments in which he gave from 
.015 gramme to .03 gramme, while in a third the arterial 

1 Compt. rendus de la Soc. de Biolog., July 1, 1887. 

3 Centralblatt fur die Medicin. Wissenschaften, No. 30, 1887. 

3 Bull. Generate de Therapeutique, Feb. 28, 1887. 

4 Therapeutic Gazette, 1887. 

4 D 



74 Fever: its Pathology and Treatment. 

pressure was slightly raised. The writer has also found 
and stated, in an earlier paper, that the circulatory influ- 
ence of antifebrin was very inconstant, and that the 
pressure and pulse are sometimes increased, sometimes 
decreased. More recently he has made other experi- 
ments, an example of which follows, in regard to this 
matter, and has reached results confirmatory of his 
earlier investigations. (See tracing No. 2.) 

In the article on antipyrin it was shown that there 
was no relation between arterial pressure, pulse-rate, and 
the fall of temperature under the influence of that 
drug, and the same facts exist in regard to antifebrin. 
Although the pressure in the normal animal tends to fall 
with the temperature, it must be remembered that with 
antifebrin, which is itself depressant to a slight extent, 
a very great fall should ensue if the fall of bodily heat 
depended in any way on the vascular changes produced 
by the drug. The charts published by the writer l in 
1887 show this very well. 

On the fevered animal there seems to be no relation- 
ship between blood-pressure and bodily temperature, 
although the influence of the drug over the fever pro- 
duced by the use of pepsin is not very powerful. At 
the same time the results reached confirm those 
made upon the normal animal in regard to this point 
and agree perfectly with the experiments of other inves- 
tigators. 

Blood. — From a toxicological and physiological point 
of view, antifebrin exerts, when given in large doses, 
more influence on the blood than upon any other part 
of the body. Added to freshly-drawn blood or to the 
blood in the body, it produces a peculiar change in the 
color, the normal red becoming brownish. Abundant 

1 Therapeutic Gazette. 




71a 



► 
a 
o 

d 
s 




74d 



©3 



g 



>3 



Pm 




74c 



Q 
O 



o 
Q 

SM 

h3 

OS 

§* 

°§ 
!« 

Q GO 

a' 
Pod 

*g 

3 

b 

o 



Q 
> 

M 
| 




74d 




Same Continued, Two 
Minutes Later. 



Same Continued, Three 
Minutes Later. 



74e 



Antifebrin : Experimental Evidence, 75 

investigation on the part of Weill, 1 Henocque, 2 Herczell, 3 
Miiller, 4 Bokai, 5 and Evans 6 has proved that toxic 
doses decrease not only the oxidizing power of the blood, 
bat also produce in it the changes which give the spec- 
trum bands of methaemoglobin. 

While unanimity exists as to the changes in color in 
the blood, no such coincidence is present in regard to 
the number and character of the blood-corpuscles under 
the influence of antifebrin. Lepine and Aubert (loc. cit.) 
claim that the corpuscles are reduced in number, but that 
their form remains unchanged ; while Herczell reports 
that they will no longer form rouleaux, but are granular, 
thinned, and non-coherent. Directly opposing himself 
to Lepine, he finds no numerical decrease. Herczell is, 
however, in accord with the French investigators in the 
statement that free coloring matter is set free in the 
blood. If this is the case there must be some loss of 
corpuscles in this dissolution, and all observers are in 
accord in the belief that the persistent use of antifebrin 
may so alter the blood as to produce death. (See " Toxic 
Action," p. 72.) 

The quantity of haemoglobin reduced b}^ antifebrin is 
very considerable. Henocque states that 6.5 per cent, 
of all the haemoglobin of the blood must be so altered 
before the spectroscope shows the methsemoglobin band. 
When it is remembered that the normal reduction of the 
oxyhemoglobin in the veins only equals 5 per cent., it is 
at once seen that the arterial blood under such circum- 
stances is less able to perform its function than is venous 
blood ordinarily. 

1 Bulletin Gen. de The'rap., Feb. 28, 1887. 

3 Compt. Rendus Soc. de Biol., Paris, 1887-88, iv, 498. 

3 Wien. Med. Wochensclirif t, 1887, 1021, 1057, 1085, xxxvii. 

4 Gazette Me'd. de Strasburg, 1886, xv, 128. 

5 Pest. Med. Chir. Presse, Budapest, 1887, xxiii, 469. 

6 Therapeutic Gazette, 1887. 



76 Fever : its Pathology and Treatment. 

According to Herczell, the alkalinity of the blood is 
decreased, the urine becomes dark and brownish in color, 
and the blood-crystals of Teichmann can be obtained 
from it. The research of Herczell is of value in that it 
also shows us how nearly related antifebrin is to aniline. 

Tissue Waste and Urine. — A great deal of contra- 
dictory evidence in regard to the influence of antifebrin 
upon tissue waste or metabolism and urinary flow has 
been given us by various investigators, chief among 
whom ma}^ be named Lepine, 1 Bokai, 2 Fasternatski, 3 
Cahn and Hepp, 4 the first clinicians to employ it, Lang 5 
and Solaro. 6 

Lepine found, in a very careful series of studies, that 
there is produced by antifebrin an augmentation in the 
excretion of urea and uric acid. Unfortunately, how- 
ever, Lepine 's conclusions are opposed to the results 
obtained by others. Bokai believes the nitrogenous ele- 
ments of the urine are decreased and that it is by this 
means (decreased tissue change) that antifebrin lowers 
fever. Pasternatski also reaches similar conclusions, 
but it is only just to say that the researches of Lepine 
surpass, in the care exercised in their performance, those 
of his opponents. 

In a series of studies carried out by Taylor, 7 under 
the direction of Chittenden, results were reached which 
support those of Lepine. This observer placed a young 
man, about 62 kilos in weight, under a condition of ni- 
trogenous equipoise, and then examined the urine for 
ten days, when antifebrin was given, and during a 

1 Lyon Medical e, April 24, 1887. 

3 Deutsche Med. Wochenschrift, Oct. 20, 1887. 

3 Vratsch, Nos. 2 and 4, 1887. 

4 Deutsche Med. Wochenschrift, No. 16, 1887. 

6 Wiener Medicin. Wochenschrift, May 29, 1887. 

6 Medica Contemporanea, 1887. 

7 {Studies from Labor. Phys. Chemistry, Yale, vol. iii. 



Antifebrin: Experimental Evidence. 77 

second period of ten days, when antifebrin was again 
employed. The dose used was a little over 6 grains a 
day at the lirst, and this was rapidly increased to 40 
grains a day, given in three doses. 

As a result of these studies, Taylor believes that 
antifebrin slightly increases the excretion of urea, while 
the amount of sulphur remains almost unchanged. It 
was also found that the excretion of phosphorus was 
unaffected by the drug. 

In the studies on the excretion of uric acid, how- 
ever, the results reached indicate a distinct inhibitory 
action on the part of antifebrin. Berezooski finds, very 
naturally, that the quantity of urea decreases with the 
fall in temperature. 

According to the remarkably careful and accurate 
studies of Muneo Kumagawa, 1 antifebrin produces, in 
the dose of 30 or 45 grains daily, no obvious alteration 
in the elimination of nitrogen in the dog ; but if as much 
as 60 to 75 grains a day are employed, then a very con- 
siderable increase in nitrogenous elimination takes place, 
the mean increase being 30.8 to 35.7 per cent. It was 
also found that the increased elimination of 46 grammes 
of nitrogen during the administration of antifebrin 
(corresponding to 1353 grammes of meat or animal 
tissue) was exactly equalled by the decreased elimina- 
tion of a similar amount during the twenty-five suc- 
ceeding days. In forty -nine da} T s of observation, during 
which very considerable loss of organic nitrogen and 
restitution of the same took place, no marked deficiency 
of nitrogen was observed. When considerable loss of 
nitrogen occurred, the sulphates followed irregularty. 

Upon the quantity of urinary flow very great differ- 

1 London Med. Record, Oct. 20, 1888. 



78 Fever : its Pathology and Treatment. 

ences in reports exist. Weill 1 reports that he found it 
greatly decreased in amount, but that sometimes no 
change occurred. He never found the quantity of urine 
increased, while, on the other hand, Cahn and Hepp, 2 
Solaro, 3 and Faust 4 assert that the urine is greatly 
increased in amount, — a conclusion which has been con- 
firmed by Osier 5 in this country. The evidence seems 
to be so generally in favor of increased diuresis that for 
the present we must accept the latter conclusion as 
correct. The writer cannot help thinking that accurate 
measurements of the quantity of water and food ingested 
would show that the drug, in reality, has very little 
influence over the quantity of urine excreted unless 
extraneous factors are at work. 

Nervous System. — The influence of antifebrin upon 
the nervous system is very marked indeed, the sensory 
portion of the nerves and cord being greatly quieted. 

From the studies of Lepine 6 and Sardina 7 we obtain 
our chief knowledge of these facts, as well as from the 
researches of Herczell. 8 These investigators have found 
that large doses of antifebrin produce great quietude 
and a general anaesthesia, followed by total loss of all 
reflexes, and finally both motor and sensory paralysis. 
The portions of the nervous system involved are 
primarily the sensory side of the spinal cord and the 
sensory nerves, the motor side of the cord and the 

1 Bulletin Generate de Therapeutique, 1886 ; also These de Paris, 
1887. 

3 Deutsche Med. Wochenscrift, No. 16, 1886. 

3 Rivista Medica Contemporanea, 1887. 

4 London Medical Record, July 15, 1887. 
6 Therapeutic Gazette, 1887, p. 165. 

6 Lyon Medicale, Oct. 31, 1886, and Semaine Me'dicale, 1886, p. 473. 
1 Contribution to the Physiological and Therapeutical Effects of Ace- 
tanilide on the Nervous System, 1887. 

8 Centralblatt fur die Medicin. Wissenschaften, No. 30, 1887. 



Antifebrin: Experimental Evidence. T9 

nerves being affected late in the poisoning or not at all. 
The drug in toxic doses does not affect the muscles, as 
has been proved by Bokai, 1 who finds a ready response 
made by them on the application of electricity ; but he 
also finds that a similar application to the motor nerves 
is absolutely without effect, the muscles failing to 
respond, proving, Bokai thinks, that the nerves must be 
paralyzed peripherally. 

Respiration. — The influence of antifebrin on respi- 
ration in ordinary doses is very slight ; but if sufficiently 
large doses are used to produce very distinct plr^siologi- 
cal or toxic effects, this vital function is at once altered 
and impaired. 

The writer also found that if as much as 1 grain 
to the pound of the animal be injected into the jugular 
vein death occurs at once, not from cardiac but from 
respiratory failure, the heart beating for some minutes 
afterward. If the dose be smaller, these effects are less 
severe but well marked, the respiratory movements 
being superficial and frequent, then irregular, arhythmi- 
cal, then noisy, then quiet. That there are several 
factors in the production of these respiratory disturb- 
ances seems positive. Primarily there can be no doubt 
but that the early alterations in the character of the 
blood so influence oxygenation as to goad the respira- 
tory centre to greater effort, while at the same time the 
centre is beginning to be directly depressed by the drug 
itself. Further than this, if Bokai's 2 assertion be true, 
namely, that the peripheral motor nerves are paralj T zed, 
then a third cause of respiratory failure comes forward 
as a factor in the changes named. 

Toxic Changes Produced by Prolonged Use. — 
Although it has been claimed by a number of clinicians 

1 Deutsche Med. Wochenschrift, Oct. 20, 1887. 2 Ibid., Sept. 2, 1887. 



80 Fever : its Pathology and Treatment. 

that no untoward effects are produced by antifebrin 
when it is taken continuously for a long time, there can 
be no doubt that this is untrue. The changes brought 
about when a single large dose is given are too positive to 
allow of any other conclusion, even if we had no other 
evidence at hand. Very recently, however, Pisemski 1 
has determined this point for us, to a certain extent, 
although his doses were very large. He found that 
when antifebrin was given by the stomach to four dogs 
in the daily dose of 2.5 grammes (37 grains), the animals 
died on the twelfth, fifteenth, sixteenth, and twentieth 
days, respectively, and the post-mortem examination 
revealed some congestion of the liver and brain, although 
the former organ was once or twice found to be very 
anaemic. The spleen was sometimes shrunken, sometimes 
normal, but the kidneys were alwaj T s congested. A 
peculiar feature of this slow poisoning was the dark, 
voluminous clots found in the cardiac cavities. 

Pisemski also noted a progressive diminution in the 
number of the blood-corpuscles from the beginning to 
the end of the tests. 

Elimination. — During the first few months in which 
antifebrin was used by the profession it was stated that 
the drug was utterly destroyed in the body, being en- 
tirely consumed, but we now know that this state- 
ment is untrue and that such a belief arose simply from 
ignorance of the alterations it is capable of undergoing. 
Miiller 2 is one of those who makes this statement. In 
a series of experiments carried out by Pavai-Vajna 3 it 
was discovered that antifebrin is eliminated as is ordi- 
nary aniline, namely, as para amido-phenol sulphate, 

1 Inaugural Dissertation, St. Petersburg, 1887, p. 48. 

2 Deutsche Med. Wochenschrift, 1887, No. 2. 

3 Centralblatt fur die Gesammte Therapie, August, 1887. 



Antifebrin : Experimental Evidence. 81 

and this observer has been confirmed by Matuzorszki, 1 
who has found this compound present in the urine even 
when very small medicinal doses are employed. Jaffa 2 
and Hilbert have confirmed these conclusions. 

As a result of these studies it at once becomes evi- 
dent that when antifebrin enters the blood it is broken 
up into acetic acid and aniline, and that this aniline is 
then changed into para-amido-phenol, which unites with 
the sulphuric acid in the body to form a sulphate. 

This belief is still further substantiated by the 
physiological action of the drug, which is very closely 
allied to that of aniline, as has been shown by Herczel 
and others. 

Cahn and Hepp, however, state that antifebrin escapes 
from the body unaltered, only a small amount under- 
going any change. 

Closely allied to this is the result reached b}^ Wen- 
driner, 3 who asserts that if a small quantity of anti- 
febrin be added to normal urine and the fluid be made 
strongly alkaline with caustic soda and distilled, aniline 
will be found in the distillate. While this is true, he 
asserts that the urine of patients taking antifebrin as a 
medicine gives no such reaction for aniline, although 
the drug is undoubtedly decomposed in the bod} r . The 
reason of this has been just pointed out, and the results 
of Pavai-Vajna and Matuzorski are supported by the 
further statement of Wendriner that the amount of 
phenol in the urine is increased. Wendriner states that 
the amount of phenol present is about 5^ per cent, of 
the antifebrin taken. 

Kumagawa 4 also asserts that neither antifebrin nor 

1 Endietol Orvoss-term. tud. Ersesito. Kol.ozsvar, 1887, p. 17. 
3 Zeitschrift fiir physiologische Chemie, 12, p. 307. 

3 Centralblatt fur die Med. Wissenschaft, No. 8, 1887. 

4 London Medical Recorder, Oct. 20, 1888. 

4* 



82 Fever : its Pathology and Treatment. 

aniline are to be found in the urine after the drug has 
been taken, and indorses the statement of Pavai-Vajna 
as to the change into para-amido-phenol sulphate. This 
same investigator found that when given internally 
antifebrin is rapidly absorbed, even in large dose, and in 
the course of twenty-four hours completely eliminated 
by the kidneys. 

Antiseptic Action. — According to Bokai 1 and Krie- 
ger, 2 antifebrin possesses decided antiseptic power, but 
their assertions are vehemently opposed by others, and 
are probably only partly correct. Lepine 3 strongly 
denies this influence, and he is supported by Dujardin- 
Beaumetz and by Miguel, the director of the micro-' 
graphic service at the Meteorological Observatory of 
Montsouris. 

Bokai noted that a 5-per-cent. solution was fatal 
to infusoria, to spirilla and bacilli, as did also Krieger. 

There can be little doubt but that in excessive 
amount the drug has some slight power of this char- 
acter, but nothing of sufficient note to be of use in prac- 
tical medicine, and Calm and Hepp 4 think that its powers 
in this direction are weak. 

According to the assertions of Kumagawa, 5 the 
drug exercises a powerful antiseptic effect in catarrh 
of the bladder and upon the contents of the intestines. 

Van Seer 6 has observed that milk does 'not become 
sour if saturated with antifebrin, and that albumen 
under such circumstances does not become putrid. 

Conclusions as to the Physiological Action of 
Antifebrin. — 1. Antifebrin lowers normal bodily tem- 
perature slightly. 

1 Deutsche Med. Wochenschrift, Oct. 30, 1887. 

3 Centralblatt fur klin. Med., No. 44, 1886. 8 Loc. cit. 

4 Loc. cit. • Loc. cit. 
6 Virchow's Archiv, Bd. cxiii, p. 184. 



Antifebrin: Clinical Evidence. 83 

2. Antifebrin lowers febrile temperature very rap- 
idly. 

3. The fail of temperature in the normal animal is 
due to decreased heat production and increased heat 
dissipation, as a general rule. 

4. The fall of temperature in the fevered animal is 
due to decreased production and increased dissipation 
of heat. 

5. Applied directly to the heart, antifebrin stops 
this viscus in diastole. 

6. Although the drug may be apparently a cardiac 
stimulant, its dominant action is that of a depressant. 

*7. It causes a decrease in pulse force and rate and a 
fall in arterial pressure. 

8. Antifebrin acts in toxic dose on the blood, chang- 
ing the haemoglobin into methsemoglobin. 

9. On the urinary flow the drug has little effect ; if 
any influence is felt the amount of urine is increased. 

Antifebrin would seem to increase tissue waste, but 
this is doubtful. 

10. Antifebrin depresses the spinal cord and motor 
and sensory nerves, but not the muscles. 

11. When toxic doses are used death is due to 
respiratory failure. 

12. Organic changes are produced by its prolonged 
use. 

13. Antifebrin is eliminated as para-amido-phenol 
sulphate. 

14. Its antiseptic powers are feeble. 

Clinical Evidence. 

When antifebrin is given in moderate medicinal 
amount to a healthy adult man, it produces, as a rule, 
no appreciable effect ; but if the amount of the drug is 



84 Feve? % : its Pathology and Treatment. 

somewhat increased, somnolence, constipation, occa- 
sional headache and nausea, with malaise and a peculiar 
dusky, cyanotic appearance, come on. 

In fevered individuals the symptoms may be much 
the same, save that frequently a great fall occurs in 
their temperature, which in some instances approaches 
collapse. 

Although these signs generally come on only when 
large medicinal amounts are given, they nevertheless 
assert themselves in persons who have an idiosyncrasy 
to the drug, and for this reason the untoward effects are 
worthy of note. 

In view of these facts the writer has collected a 
number of such instances, and has tabulated them in 
the following pages. From these it will be seen that 
the most frequent untoward effect was collapse with 
symptoms of depression, accompanied by cyanosis and 
rigors. 

The age and sex in which such symptoms showed 
themselves may be tabulated as follows : — 

Males. Females. 



1 to 10 


pears 


, 2 cases. 


1 to 10 years 


, 1 case. 


10 to 20 


ii 


8 cases. 


10 to 20 


i< 


3 cases. 


20 to 30 


ti 


4 cases. 


20 to 30 


ii 


5 cases. 


30 to 40 


II 


3 cases. 


30 to 40 


ii 


4 cases. 


40 to 50 


a 


no case. 


40 to 50 


ii 


no case. 


50 to 60 


a 


no case. 


50 to 60 


u 


1 case. 


60 to 70 


a 


no case. 


60 to 70 


II 


no case. 


70 to 80 


ii 


no case. 


70 to 80 


II 


no case. 



A large number of the reported cases did not have 
the name and sex given in the original report. 

The dose, as will be seen, was generally a moderate 
one, from 3 to 10 grains, although rarely it was much 
larger. 



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Antifebrin: Clinical Evidence. 91 

The result of an analysis of these reports is very 
reassuring to those who have patients so affected, 
for in only 3 cases did death occur. In 1 of 
these the dose was a single one, exceedingly large in 
amount ; in another, the drug was used in large doses 
during twenty-four hours ; while in the third the real 
cause of death was thought to be heart-clot. In no 
instance, therefore, did death occur from an ordinary 
dose in an uncomplicated case. 

In regard to the diseases in which untoward effects 
are most commonly seen, we find that the following list 
answers this question very well : — 



"Fever," . 
Typhoid fever, 
Miliary tuberculosis, 
Intermittent fever, 
Headache, . 
Tonsillitis, . 
Gastric fever, 
Acute gastritis, . 
Phthisis, 
Not stated, . 
Pneumonia, . 
Typhus fever, 



1 case. 
7 cases. 
1 case. 
1 case. 
5 cases. 
1 case. 
1 case. 

1 case. 

2 cases. 

1 case. 

2 cases. 
1 ease. 



As in the tables of the untoward effects of antipyrin, 
so here do we find that the reporters so frequently failed 
to mention the temperament of the patient and his occu- 
pation that too little material can be obtained from 
which to make any calculations as to these points. 

Use in Fever. — The employment of the drug anti- 
febrin in fevers must depend very much upon the exact 
condition of the patient and the form of his disease. As 
has already been pointed out, the mere presence of a 
malady, or of a high temperature, cannot, correctly 
speaking, be an indication for any particular remedy. 



92 Fever: its Pathology and Treatment. 

The phase of the disease must be recognized and the 
question as to whether the fever which is present is 
harmful must be duly weighed. If such attention is 
not paid we at once have to do with the bane of medi- 
cine, — meddlesome therapeutics. 

Though a number of writers have claimed that cer- 
tain antipyretic remedies of equal power act with differ- 
ent results in different diseases, the writer has never seen 
an}^ such differences, and we must be guided rather b}< our 
individual experience as to the value of some particular 
antip3^retic in all diseases than by any other rule. The 
question is rather what is the best antipyretic for all 
cases than what is the best one to use in this or that 
case, provided, of course, that no idiosjaicrasy exists 
to any one of them. 

All observers are not in accord, however, as to which 
is the best antipyretic. While the writer has heard 
phenacetin spoken of most highly b}^ some authorities, 
he has heard it equally severely condemned by others ; 
and though Ringer prefers antipyrin, Mitchell Bruce 
relies chiefly upon antifebrin. In America almost every 
one prefers the former drug, and the general diffusion 
of this preference apparently rests not so much upon 
published facts as upon personal experience. While the 
number of cases of ill effects recorded is small with 
antifebrin as compared with those of antipyrin, the idea 
prevails, and perhaps justly, too, that the former is 
much more capable of harmful deeds than the latter, 
and it cannot be denied that scientific basis of great 
weight exists for this belief. 

According to Eisenhart, 1 the antip}^retic influence 
of antifebrin is not manifested for fully two hours 
after its administration, when it appears with a profuse 

1 Miinchener Med. Wochenschrift, No. 47, 1886. 





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Temperature Chart of Case of Typhoid Fever, showing 
that antifebrin is not so powerful an antipyretic 
as ant1pyrin. 



(93) 





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Temperature Chart of Case of Typhoid Fever in which 
Antifebrin Produced a Good Effect. 



(94) 



Antifebrin: Clinical Evidence. 95 

perspiration, and, sometimes, collapse. He concludes 
that small, repeated doses are useless ; that to obtain any 
good results we must use all we wish to at one time, and, 
if no fall of temperature occurs, resort to some other 
remedy. 

That Eisenhart is correct in these views has not 
only been proved by the writer, but by the original 
users of the drug, Calm and Hepp, 1 and by Heinzel- 
mann, 2 Lang, 3 and Lepine. 4 As a rule, the dose of the 
drug used by these clinicians was from 4 to 8 grains, 
although Lepine has given the enormous quantity of 1 
drachm. 

Typhoid and Other Low Fevers. — In t} T phoid fever 
the studies of most clinicians show that, though the 
drug possesses very decided antipyretic power, it often 
causes great depression and collapse, and in no way 
influences the duration or general course of the disease. 
How much this result has been due to the excessive 
employment of the drug is doubtful, but that it has 
been so abused seems evident, when we find that Lepine 5 
recommends the use of 8 grains an hour, before the time 
when the rise of temperature is expected, though he 
confesses that in those seriously ill he has seen cyanosis, 
with a lessened amount of urine, assert itself as a result 
of such methods. In the same manner, Mousset, 6 who 
worked under Lepine, recommends two such doses daily, 
and a third as soon as the system becomes accustomed 
to the druo\ According- to the statements of Mousset 
himself, such a method of treatment produced cyanosis 
in no less than 3 out of 7 cases. 

1 Centralblatt fur klin. Med., Sept., 1886. 

2 Miinchener Med. Wochenschrift, No. 3, 1887. 

3 Wien. Med. Presse, May 29, 1887. 

4 La Seinaine Me'd., p. 473, 1886. 

8 Ibid. 6 Lyon Me'dicale, 1886, liii, p. 309. 





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Temperature Chart of Case of Typhoid Fever in which 
an Excessive Dose was Administered through an Error 
on the part of a Nurse. 
(96) 



Antifebrin : Clinical Evidence. 97 

The sweating, sometimes produced in excessive 
amounts, may prove a just cause for the non-employ- 
ment of the drug in typhoid fever. Numerous cases 
have come under the author's notice where this state 
existed, and Osier has noted that the profusion of the 
sweat may be so great as to utterly prohibit its use. 

By far the most exhaustive study of the effects of 
antifebrin in t} T phoid fever that we have seen is that of 
Guttmann, 1 who treated no less than 81 cases with the 
drug, giving 7 grains night and morning, except at about 
the twelfth or fourteenth cky, when one dose was suf- 
ficient. He thinks that small, repeated doses are useless 
and without any effect, yet so confident is he of the 
power of the drug in doing good, if used properly, that 
he thinks it quite as efficacious as the cold bath, and 
better, in typhoid fever, than any other remedy of its 
class. 

The reason for Guttmann's preference for antifebrin 
to antipyrin is found in the diminutive dose of the former 
as compared to that of the latter, for he states that he 
discovered that it required as much as 60 or 70 grains 
of antipyrin twice a day to produce the effects seen 
after the use of 7 grains of antifebrin, night and morn- 
ing. He also noted that the apyrexia of antipyrin only 
lasted about four hours, while that of antifebrin was of 
much longer duration. 

On the other hand, it is claimed by Secretan 2 that 
the reverse is the case, and that antipyrin is far superior 
to antifebrin in the permanence of its action. Demme 3 
also makes a similar assertion, and the writer, from his 
own observations, is inclined to agree with him. Very 

1 Berliner klin. Wochenschrift, 1887, p. 942. 
Q Revue Medical e de la Suisse Romande. 1886. 
3 Internationale Klin. Rundschau, No. 4, 1888. 
5 E 



98 Fever : its Pathology and Treatment. 

frequently in the St. Agnes Hospital this fact has been 
noted, and Guttmann is certainly incorrect in his asser- 
tions. At the same time, the writer must confess that 
his experience is fully in accord with that of Guttmann 
in respect to the effect of large doses given at long inter- 
vals ; in every instance where the two methods have 
been tried by the writer the small doses, frequently 
repeated, have failed, where the others produced an effect 
not only of a much more marked character, but more 
prolonged. That Guttmann has the support of some cli- 
nicians is undeniable, but that certain investigators have 
obtained good results from small, frequentty repeated 
doses cannot be gainsaid. Thus, Way 1 has so used 
antifebrin in 13 cases of typhoid fever and reached good 
results. He thinks that the effective dose is so small as 
compared to the poisonous dose as to make the drug 
perfectly safe. A study similar to that of Guttmann, 
made by Faust, reached results of a satisfactoiy charac- 
ter, the drug being used in 29 cases of enteric fever. 
Faust noted, when the temperature rose rapidly and 
was accompanied by a chill, that he was able to pre- 
vent this exacerbation by a dose of the drug, just as the 
rigor was beginning. Curiously enough, he is also 
responsible for a recommendation which flavors of similia 
similibus curantur, which we cannot understand, namely, 
that the use of a small amount of antifebrin immediately 
after the use of the cold bath in typhoid fever prevents 
any subsequent chilliness and quiets the patient. If 
this is true the drug must exert a balancing power over 
the heat-centres. 

We have already spoken of the fact that all writers are 
in accord in stating that antifebrin does not influence the 

* Medical News, 1887, vol. i, p. 241. 



Antifebrin: Clinical Evidence. 99 

duration or course of typhoid fever except by an indi- 
rect action. It is, however, very important for us to 
discover whether the condition of the patient is for the 
time being really improved. The writer is sure that the 
answer should be in the affirmative, and there is an 
overwhelming amount of testimony in favor of such a 
belief. Thus^ Faust found that all his cases felt bet- 
ter, seemed more intelligent, and had a cleaner-looking 
tongue, with less anorexia, when the drug was used. 
Calm and Hepp have also stated that the peculiar 
drowsy, stupid face of such cases brightens up if the 
drug is given, and there can be no doubt but that this 
is true. 

While antifebrin has been greatly praised by writers 
in Europe, in America it has not been thought of 
so highly. Cohen, 1 in an article upon its employment 
in typhoid fever, has done anything but praise it, as he 
found it far more dangerous than antipyrin. He also 
noted that it was less enduring in its effects, — a conclu- 
sion which agrees with the statement of Demme and 
Secretan, already given. Greene 2 has recorded instances 
in which the drug absolutely failed where antipyrin 
succeeded, and the writer has frequently turned from 
antifebrin as useless, in safe doses, to receive aid from 
the antip} T rin. 

The value of antifebrin in phthisis is doubtful, since, 
although it greatly affects the temperature, it is very 
apt to cause collapse, profuse sweating, and depression. 
Thus, the writer has seen cases of phthisis where the 
attempt to control the fever by antifebrin resulted in 
the manner named, and Riese 3 points out, what the 

1 Medical News, Oct. 8, 1887. 

2 University Med. Magazine, Jan., 1889. 

8 Deutsche Med. Wochenschrift, 1886, 83-5. 



100 Fever : its Pathology and Treatment. 

writer has also noted, namely, that in this disease cy- 
anosis is very apt to come on. Weill 1 also believes it 
is contra-indicated in tubercular hectic fever, and in this 
he is indorsed by Pavai-Yajna. 2 On the other hand, 
Cauldwell, 3 after trying it in 30 cases, came to the con- 
clusion that it is the best drug with which to combat the 
fever and accompanying evils of phthisis. In the face of 
such contradictory testimony some confusion arises, but 
the author is confident that he is correct in believing it 
harmful rather than of good effect. 

Sthenic Fevers. — It at once becomes evident to the 
most careless student of medicine that a drug abso- 
lutely unsuited to a case of asthenic disease may, on 
the other hand, agree with a scarlet-fever patient very 
well, or that the reverse may be true. 

In consequence of this we find that the sweating of 
antifebrin is not marked or troublesome in acute 
sthenic diseases, and that in consequence it more rarely 
causes collapse. In measles and scarlatina both Gins- 
burg and Widowicz 4 speak highly of its use, and the 
former thinks it is better under such circumstances than 
is antipyrin. That these assertions are based upon fact 
seems positively proved, and that there is a reason for 
them is also apparent. 

Most of the exanthematous diseases are those of 
childhood, and there is a vast amount of clinical evi- 
dence showing that these drugs are particularly effica- 
cious and devoid of untoward influence in young 
persons. Lowenthal, 5 Demme, 6 Love, 7 and Guttmann, 

1 Tribune Me'dicale, 1887, xix, 195. 

3 Centralblatt fur die Gesammte Therapie, 1886. 
8 N. Y. Medical Record, 1887, xxxi, p. 426. 

4 Wien. Med. Wochenschrift, 1887, p. 529. 

6 Therapeutische Monatshefte, Sept., 1887. 

6 Internationale Klin. Rundschau, No. 4, 1887. 

7 Journal American Medical Association, 1887. 



Antifebrin : Clinical Evidence. 101 

as well as myself, have found this to be the case. In 
small-pox Haas has found that in confluent cases anti- 
febrin lowers the temperature and relieves the nervous 
irritation, altogether exercising a desirable influence. 

Rheumatism. — The employment of antifebrin in 
rheumatism may be separated, if desired, into that de- 
voted to the cure of the disease with the relief of pain 
and the reduction of pyrexia. There can be no doubt 
whatever of the ability of the drug to control the fever of 
this disease, but the question as to whether it favorably 
influences the progress of the malady is to be decided. 

We have already spoken of the studies of Guttmann 
upon the antipyretic power of antifebrin, but it should 
not be forgotten that he has also used it far more in 
rheumatism, 1 as he has employed it in 52 cases of acute, 
29 cases of chronic articular rheumatism, and in 167 
cases of " general rheumatism," making in all no less 
than 248 cases. The conclusions which are to be 
drawn from this immense mass of material seem to be 
that as a specific against the disease the remedy is equal 
to salic} T lic acid, antipyrin, and salol, and in some direc- 
tions seems even better than they are. The close used by 
Guttmann was from 7 to 15 grains once or twice daily, 
and he records the fact, which is scarcely credible, that 
in none of these cases did cardiac involvement ensue. 
Guttmann is supported in these statements by the ex- 
perience of Calm and Hepp, 2 Landgraf, 3 Riese, 4 Moore, 5 
Munn, 6 Destree and Slosse, 7 Charpentier, 8 Faust, 9 and 

1 Berliner klin. Wochenschrift, Dec. 12, 1887. 

2 Ibid., 1887, xxiv, p. 26. 

3 Deutsche Med. Wochenschrift, 1886, No. 47, p. 839. 
* Ibid., 1886, xi i, 835. 

6 Weekly Medical Review, April 28, 1887. 

6 Physician and Surgeon, Sept., 1887. 

1 Journal de Med. de Chirurg. et de Pharm., June 20, 1887. 8 Ibid. 

9 Deutsche Med. Wochenschrift, 1887. 



102 Fever: its Pathology and Treatment. 

Pavai-Vajna, 1 who believes it equal to salicylic acid. 
Weinstein 2 believes antifebrin to be a specific in rheu- 
matism. 

Somewhat opposed to these testimonials are the 
conclusions of Eisenhart, 3 Fadella, 4 and Poutta, as 
well as those of Lepine, 5 Snj^ers, 6 and Sarda, 7 who be- 
lieve that antifebrin, while possessing antirheumatic 
virtues, is, nevertheless, far inferior to the salicylates. 
From the author's own studies of a large number of cases 
of rheumatism, he is forced to take a position half-way 
between the opinions just given. He has seen cases of 
acute articular rheumatism improve remarkably under 
antifebrin, and he has also seen it fail as utterly. The 
two following cases are illustrative of this : — 

Case 1. — M. T., aged 45, male. Was admitted to the 
writer's wards in the St. Agnes Hospital for a severe 
attack of acute articular rheumatism. The left elbow 
was greatly swollen and inflamed, and a bursitis had been 
set up. Both feet and ankles were greatly enlarged. 
The lumbar muscles were also affected and the left 
hand was badly swollen. Antifebrin, in the dose of 5 
grains three times a day, rapidly relieved him, so that 
he was able to be out of bed on the fourth day. 

Case 2. — S. A., aged 19, domestic. Was admitted 
to the same wards in the St. Agnes Hospital for acute 
articular rheumatism, involving the left arm and both 
knees. There was a systolic murmur at the mitral 
valve. Antifebrin in 5-grain doses three times a day 
had no effect. 

1 Centralblatt f. die Gesammte Therapie, Aug., 1887. 

3 Wiener Med. Blatt., 1887, 159, 200. 

8 Miinchener Med. Wochenschrift, Nov. 23, 1886. 

4 Osservator Turin, 1887, p. 409. 

6 Lyon Medicale, 1886-87, iii, p. 269. 

6 Annales Soc. Med. Chir. de Liege, 1886, xxv, p. 499. 

7 Bull. Ge'n. de The'rapeutique, May 30, 1888. 



Antifebrin: Clinical Evidence. 103 

It is but just to say that nothing else did her any 
good as far as we could tell. Sixty grains of salicylate 
of sodium a day were ineffectual. 

These 2 cases show just what the author's experience 
has been in many instances. We must regard antifebrin 
as one of the drugs to be tried in all cases. 

Nervous Affections. — In much the same manner as 
antipyrin was found, some time after its introduction, 
to be possessed of pain-relieving power, so antifebrin 
has also been discovered to possess similar properties, — 
a discovery the credit of which must be given to the 
French investigator, Lepine, 1 who has written upon 
this subject, at various times, very exhaustively. Al- 
most every form of nerve-pain seems to indicate its 
employment, and it has been successfully used in the 
crises of ataxia, the agonizing dartings of gastralgia, 
and even in chorea, with good results. In a corre- 
sponding manner Secretan 2 has obtained brilliant effects 
in cases of sciatica, and Silva 3 has seen the most obsti- 
nate headache yield to its influences. 

One of the best papers on antifebrin as a nervine is 
that of Demieville, 4 who studied a series of cases with 
considerable care. He has shown that within half an 
hour after its administration the relief from the pain 
begins to appear, and that by one hour or two hours 
total relief is attained. Signe, under Grasset's direc- 
tion, has reached similar results, and Dujardin-Beau- 
metz 5 is loud in the praises of the analgesic effects 
obtained by him. In a similar manner Fischer, 6 of 

1 Revue de Medecine, 1886. 

2 Revue Med. de la Suisse Romande, 1887, vii, 29. 

3 Western Medical Reporter, 1886. 

4 Revue Med. de la Suisse Romande, June 15, 1887, p. 305. 

5 Therapeutic Gazette, vol. x, 1887. 

6 Miinchener Medicin. Wochenschrift, No. 23, 1887. 



104 Fever: its Pathology and Treatment. 

Canstatt, in 10 cases of tabes dorsalis, corroborates the 
views just expressed, for among the 10 cases to whom 
the drug was given ninety times it failed only once. 
In hemicrania and in " brow ague " it also seems to be 
of service, and it would be hard to find a more wide- 
spread indorsement of any drug for the relief of pain 
than is made of this one. 

Thus, Humston, 1 Clark, 2 Hirsch, 3 Talcott, 4 Adem- 
ski, 5 Munn, 6 Warfringe, 7 Stewart, 8 Merkel, 9 Mor- 
ton, 10 Proudfoot, 11 McConnell, 12 Huthins, 13 and a 
number of others have published statements to this 
effect. 

Antifebrin has also been found of value in epilepsy 
by the writer, Borosnyoi, 14 Fischer, 16 Salm, 16 and 
several others. 

1 Medical and Surgical Reporter, January 14, 1887. 

2 Chicago Medical Times, September, 1887. 

3 Therapeutische Monatshefte, October, 1887. 

4 Chicago Medical Times, October, 1887. 
6 Vratch, No. 27, 1887. 

6 Physician and Surgeon, September, 1887. 

7 Hygeia, Stockholm, August, 1887. 

8 Canada Medical Record, January, 1887. 

9 Munchener Med. Wochenschrift, June 12, 1887. 

10 American Practitioner and News, January 21, 1887. 

11 Canada Medical Record, January, 1887. 

12 Ibid. 

13 Weekly Medical Review, May 19, 1887. 

14 British Med. Journal, April 28, 1887. 

15 Loc. cit. 

16 Neurologische Centralblatt, 1886. 



THALLIN. 
Experimental Evidence. 

Although thallin is a very much older drug than 
antifebrin, being a contemporary of antipj^rin, yet our 
knowledge of its physiological action is as yet very 
limited, as are also, indeed, our clinical observations. 
For some unknown reason this drug has been placed in 
the background largely without sufficient cause, since 
very few legitimate claims are made against it, and a 
large number of reliable clinicians have spoken of it in 
high praise. 

Heat Functions. — In a very extended series of 
experiments carried out by Tschistowitsch 1 with thallin 
upon rabbits and. dogs, he found that when the drug 
was given to normal afebrile animals in the dose of 
from i to ^ grain for each 2J pounds of the animal's 
weight, or, in other words, when a dose was used which 
approached in its proportions those commonly employed 
in clinical medicine, no marked or constant change en- 
sued in the bodily temperature, although the tendency 
was naturally toward depression rather than exacerba- 
tion. It is also asserted by this observer that he 
could find no direct relationship existing between the 
quantity of the drug emplo3 r ed and the fall of tem- 
perature produced. As the research of Tschistowitsch 
seems to have been most carefully carried out, the 
writer has not thought it necessary to repeat his experi- 
ments, particularly as he used the drug by the stomach, 
the rectum, intra-venously, and subcutaneously. As he 

1 Ieshenedjelnaja Klinitscheskaja Gazeta, No. 30, 1885. 

5 * (105) 



106 Fever: its Pathology and Treatment. 

employed two varieties of animals, there can be no 
doubt of the correctness of his results, and they have 
been confirmed by Jaksch, Pisenti, and Maragliano. 

Passing on from the question as to the influence of 
thallin upon normal bodily heat, we find that in the 
fevered animal as well as in man the drug acts with very 
considerable power, and in direct proportion to its 
dosage. Not only have we the experiments of Tschisto- 
witsch on this point, but, in addition, we learn from 
those of Martin 1 that such a fall takes place even though 
the febrile action is dependent upon an injury to the 
inhibitory heat-centre of Ott in the corpus striatum. 
The very large amount of clinical evidence confirmatory 
of these statements renders them incontrovertible, and 
it only remains for us to know how this fall in bodily 
heat is brought about. From the experiments of Mar- 
tin, in the research already referred to, we find that the 
fall of temperature in the fevered dog is produced by an 
increase in heat dissipation in every instance, although 
it is to be noted that in two of the six experiments made 
by him the drug failed entirely to control the fever. It 
was also found by Martin that thallin influenced heat 
production very irregularly. In three instances it was 
increased and in three diminished. It would therefore 
appear that the chief action of the remedy is its influence 
on the elimination and not on the manufacture of heat 
units. 

In a series of studies, which seem to be of little value, 
Anserow, in the Russian Medical Review for April, 1886, 
found that, pari passu with the internal fall of tempera- 
ture in the dog, under thallin, a rise of temperature in 
the paw and peripheral portion of the body occurred ; 
and, without any good reason, he comes to the conclu- 
1 Therapeutic Gazette, May, 1887. 



Thallin: Experimental Evidence. 107 

sion that this phenomenon is due to an exhaustion of 
the heat functions of the body, — a conclusion at once as 
remarkable as it is unfounded and unnecessary, since the 
mere dissipation of heat from the periphery of the body 
may temporarily cause such a condition. 

Circulation. — The influence of thallin upon the cir- 
culation in the lower animals, when in a healthy state, 
varies, very naturally, with the dose exhibited. As may be 
seen from the tracings which follow (pages 108a to 108/), 
the drug causes a fall of arterial pressure, with an ac- 
companying slowing of the pulse, when injected intra- 
venously in full dose. As these results are but a counter- 
part of those of Tschistowitsch, they may be accepted 
as well founded and correct. 

That the influence on the circulation in moderate 
amounts is, however, very slight, is shown not only by 
the tracings herewith appended, but by the assertions 
of the Russian investigator, who has found very slight 
alterations in blood-pressure in fevered animals. 

The fall of blood-pressure when large doses are 
employed is due to direct depression of the peripheral 
vasomotor system, and, to a slight extent, to a depres- 
sion of the heart itself. 

Antiseptic Action. — Tschistowitsch has noted that 
a solution of one-tenth of 1 per cent, of thallin prevents 
the alcoholic fermentation of grape-sugar, and that a 
solution of 5 per cent, absolutely inhibits such changes. 
These results have been indorsed by those of Kries, who 
has found that a 4-per-cent. solution is capable of de- 
stroying microbes, and Goll has put the subject to a 
practical test by using the drug in a 2-per-cent. solution 
for the treatment of gonorrhoea. Similarly, Pisenti, in 
Albertoni's laboratory, has found thallin to possess prop- 
erties which prevent the putrefaction of urine. 



108 Fever : its Pathology and Treatment. 

Toxic Effects from Prolonged Use. — Very few 
reports of such a condition as this heading indi- 
cates are on record, and one of the most interesting of 
these is that of Ehrlich, 1 in which a case was given 
thallin in small, but frequently repeated, doses for forty- 
two days. At the post-mortem examination the kidneys 
were found greatly enlarged and covered by numerous 
white spots. The ends of the papilla were also covered 
by a hemorrhagic, discolored deposit. That such 
changes are produced by thallin seems proved by the 
fact that Ehrlich has seen exactly similar changes in 
dogs under the same conditions. 

By far the most complete studies upon this question, 
however, are those of Pisemski, 2 who, giving the drug 
hypodermically, found that in rabbits, in the daily dose 
of 3 grains, death ensued on the sixteenth to twenty- 
eighth day, or, if the dose was 6 grains, the animal died 
in one day. In the dog it was found that the daily dose 
of 5 grains produced death in twenty-five to twenty- 
eight da} r s. 

The changes found post-mortem by Pisemski were 
as follow : In the brain, lungs, spleen, liver, and kid- 
neys there were detected, side by side with intense 
congestion, quite distinct inflammatory and degenerative 
changes in the early stages, while at the same time a 
general decrease in bodily weight was most noticeable. 
Before death it was found that the constant use of the 
drug caused a primary increase, followed by a decrease, 
in the number of the red blood-corpuscles, which 
decrease ultimately was very great. 

Pisemski also concludes that thallin exercises a much 
more irritant action on animal tissues than antip3 T rin. 

1 Centralblatt fur die Med. Wissenschaften, Oct. 1, 1887. 

2 St. Petersburg Inaugural Dissertation, 1887, p. 48. 




108a 




1086 




108c 




iOSa 




106e 




108/ 



TJiallin: Experimental Evidence. 109 

Tissue Waste and Elimination. — Upon tissue waste 
thallin seems to have comparatively little effect. Kuma- 
waga 1 has found that in the healthy clog there is an 
increased elimination of nitrogen (mean increase, 6.6 
per cent.). On the other hand, Karst, 2 in some experi- 
ments upon afebrile and fever patients, found that the 
daily amounts of urine and urea were considerably les- 
sened, the urine becoming strongly alkaline in reaction, 
and he therefore thinks that the drug inhibits the elimi- 
nation of oxidation products. These results are par- 
tially confirmed by Britneff, 3 who found the amount of 
urine decreased, with a rise in specific gravity to 1033, 
indicating increased solids. 

On the other hand, Livierato and Predazzi 4 assert 
that thallin does not influence the quantity of urine 
passed, but that a single dose of 7 grains may cause a 
diminution of 5 grammes of urea in twenty-four hours, 
and that still larger doses cause a still greater diminu- 
tion. 

Upon the amount of C0 2 given off by the lungs, a 
dose of 15 grains caused a decrease of 6 grains of C0 2 
for ever}' 2 pounds of bodily weight. 

Robin 5 has studied the effects of thallin upon the 
urine very thoroughly, using as subjects for his research 
4 old men of from 61 to 68 years. All of them were 
in perfect health, although 2 of them showed slight 
evidences of arterial sclerosis. The doses used were 
from 15 to 45 grains, and the estimations were made 
of the uric acid, potash, sulphur, and phosphorus 
compounds. 

1 London Medical Recorder, Oct. 20, 1888. 

2 Vratch, No. 2, 1886, p. 32. 

3 Russkaia Meditzina, No. 1, 1886, p. 6. 

4 La Medica conteniporania, July, Aug., and Sept., 1885. 

5 Archives de Physiologie, No. 4, Oct., 1889. 



110 Fever : its Pathology and Treatment. 

Upon the quantity of the urine, Robin found that 
the general tendency was to decrease the amount ex- 
creted daily, and out of 5 experiments there was only 1 
which was not so influenced by the drug. After the 
drug was stopped the quantity of urine returned to the 
normal amount or above it. 

Rather curiously, the statement is made that the 
specific gravity of the urine is lowered by the drug, 
although the amount of urine is decreased while the 
drug is taken. After the drug is stopped the specific 
gravity returns to normal. The amount of nitrogen 
eliminated is always diminished by thallin and the uric 
acid is also similarly decreased. In regard to the influ- 
ence of thallin upon the phosphoric acid thrown off, 
Robin reached contradictory results, for in 2 cases this 
acid was decreased and in 2 increased. The sulphates 
were at first diminished, then increased, and the carbolic 
acid of the urine diminished during the use of the drug, 
but increased later on. 

Robin believes that the formation of nitrogenous 
substances from tissue break-down is increased hy the 
drug, but that their elimination is decreased, and that, 
in consequence, the drug is a dangerous one. 

The drug is rapidly absorbed and rapidly eliminated 
by the kidneys as a combined sulphate, even when given 
in excess. 

According to von Jaksch, 1 the addition of per- 
chloride of iron to the urine produces an emerald-green 
color, and this reaction may be obtained as early as one- 
half hour after the introduction of the drug into the 
mouth, while b}^ forty -eight hours all the drug is elimi- 
nated, according to Jaksch. Maragliano, however, found 

1 Wiener Med. Wochenschrif t, 1884, No. 48. 



Thallin: Clinical Evidence. Ill 

nearly all of it eliminated in ten hours and none of it 
present after twenty hours. 

Conclusions as to the Physiological Action of 
Thallin. — 1. Thallin causes a slight fall in normal bodily 
heat. 

2. Thallin would seem to lower febrile temperatures 
by increasing heat dissipation. 

3. On the circulation the drug has a slight depress- 
ant effect, but this is of little moment. The fall of 
pressure occurring after large doses is due to a 
depression of the heart and vasomotor system. 

4. Thallin in the amount of a 1-per-cent. solution 
possesses antiseptic power. 

5. Given for a long time in toxic doses, it produces 
death, with internal congestions and degenerative 
changes in the kidneys. The blood-corpuscles are 
decreased in amount. 

6. Upon tissue waste thallin exercises an inhibitory 
influence, according to some observers, and an acceler- 
ating effect, according to others. The urine is generally 
decreased in amount. 

7. The drug is rapidly eliminated. 

Clinical Evidence. 

There are three salts of thallin, — the sulphate, the 
hydrochlorate, and the tartrate. All of them are much 
alike in general appearance and taste, but the sulphate 
is the salt most commonly employed in medicine. 

Given to man in a healthy state, they produce an 
unpleasant taste, but no other ill effect, unless the dose 
has been very large ; the ordinary amount of from 7 to 
11 grains scarcely produces any signs at all. According 
to Maragliano, as much as 6 grammes may be taken in 
six hours without producing any gastric disturbance. 



112 Fever : its Pathology and Treatment. 

Buzzing in the ears may come on from large doses, and 
poisonous amounts produce labored respiration, deep 
c^yanosis, and coma. 

The only study of much value that we have is that 
of Maragliano, made upon healthy persons. He found 
that in ap} T retic individuals the arterial pressure does 
not present appreciable modifications under its use, save 
that for the first hour after its administration there is 
a slight tendencj^ to rise, and in the second hour to fall. 
On the heart he thinks thallin acts as a tonic, rather 
than as a depressant. These results have been confirmed 
by the writer and by Pisenti upon the dog and rabbit 
(see u Experimental Evidence"), and are undoubtedly 
correct. 

Fever. — The chief students of the action of thallin 
upon fever in the human being are its champion, Jaksch, 1 
Maragliano, 2 Griffith, 3 Minot, 4 Nothnagel, 6 Ehrlich, 6 
and Laquer, as well as Guttmann, Welt, Demuth, 
Oppler, Stegen, and others, among whom may be men- 
tioned Demme and Jaccoud. The* studies of Minot 
seem, owing to their American origin and care, worthy 
of special mention, as in reality outlining the general 
opinion and thought of practitioners on this side of 
the Atlantic. Minot found that thallin acted most sat- 
isfactorily and with the most lasting effect when it was 
given at, or just before, the end of the fastigium. The 
effects of the drug were always most favorable, sweating 
and vomiting occurring but a few times, while in many 
instances the patient, previously restless and delirious, 

1 Wiener Med. Wochenschrift, 1884, No. 48. 
8 Gazetta degli Ospitali, July 5. 1885. 

3 Annual of the Universal Medical Sciences, 1888. 

4 Transactions Assoc, of American Physicians, 1887. 
6 Allgemeine Wiener Med. Zeitschrift, 1887. 

6 Berliner klin. Wochenschrift, Nos. 51, 52, 1885. 



Thallin: Clinical Evidence. 113 

became tranquil and quiet. It was also found b}^ Minot 
that the drug exercises no appreciable influence upon 
the duration of the disease in typhoid fever, and he 
concludes that it is sufficiently harmless to be given to 
very young children. 

The author's experience with thallin is too limited 
to admit of his speaking authoritatively concerning it, 
and he will therefore o\\\y state that it has alwa} T s 
seemed to him far less useful in fevers than many of the 
other drugs of its class. The fact that its action is so 
transient, — only lasting two or three hours, as a rule, — 
the necessity of its frequent dosage in consequence, and 
its liability to nauseate the patient, by reason of its 
taste and action on the stomach, are all against it. 
That it acts quite as rapidly, if not more so, than anti- 
pyrin and antifebrin, there can be no doubt. It has 
been found, too, that the sweat is often very excessive, 
although there are some observers who assert that in 
children, particularly, this S3 T mptom is often absent. 
Jaccoud thinks that so many people have an idiosyn- 
crasy to its use that small doses should alwaj-s be used 
at first. 

Owing to the transitory effects of the drug, repeated 
administrations of the remedy are necessary, and, 
as this fact was first pointed out by Ehrlich, the term 
" thallinization of Ehrlich" is frequently heard of 
at the present time when the drug is spoken of. The 
doses should be given hourlj' , in the amount of \ to 1 
grain, or even 2 grains, to adults whenever it is desired 
to thallinize a case. In every instance its action should 
be carefully watched. 



E* 



PHENACETINE, OR ACETPHENITIDIN. 

Experimental Evidence. 

The discovery on the part of Hinsberg and Kast 1 
that a compound known to chemists as acetphenitidin 
possessed antipyretic powers led them to employ the 
drug in cases of disease. 

Unfortunately, our knowledge of its physiological 
action is most limited, and until very recently it has 
been almost entirely confined to the original studies 
made upon animals by the investigators just named. 

Heat Functions. — Fortunately for our knowledge of 
the influence of phenacetine upon heat functions, Ott, 2 
of Easton, Pa., has carried out and published an appar- 
ently thorough research upon this question, and, as the 
calorimeter was used, his conclusions may be accepted 
as correct. 

As a result of these studies we now know that phen- 
acetine lowers febrile temperature by decreasing heat pro- 
duction with an accompanying decrease in heat dissipa- 
tion. That these results are due to an action upon the 
nervous heat-centres is proved not only by our physio- 
logical knowledge, but by the fact that the febrile process 
was produced by puncture of these centres, and that no 
change occurs in the blood-pressure, under the influence 
of the drug, to account for any vasomotor palsy, with 
resulting loss of heat. 

Circulation. — Upon the circulation phenacetine acts 
with comparatively little power, and it requires large 
doses to produce toxic effects. 

1 Centralblatt fur die Gessammt Therap., April, 1887. 
3 Journal of Nervous and Mental Disease, p. 598, 1888. 

(1H) 



Phenacetine: Experimental Evidence. 115 

In the following tracings (pages 116a to 116e) this is 
very evident, and it will be seen that even the largest 
dose given had no great effect upon the pulse-rate or 
blood-pressure, even though the amount used was ex- 
ceedingly large when compared with the size of the 
animal. The same facts have been noted in man, and 
they are undoubtedly correct. 

Blood. — When doses of from 15 to 30 grains of 
phenacetine are given to dogs, or any of the lower ani- 
mals, the blood soon becomes darkened in hue, but no 
important symptoms seem to be produced. It has been 
proved by Hinsberg and Kast that this darkened blood 
is due to the presence of methaemoglobm, but they also 
assert that the spectrum band of this altered compound 
is often absent on examination, even though the blood 
be dark. The reason for this absence is easy to discover 
when we remember that the spectrum of methsemoglobin 
does not appear unless this compound is present in 
excess, and, as a consequence, only very large doses of 
phenacetine can produce it in sufficient amount to be 
spectroscopically recognized. The very fact that the 
drug is so closely allied to antifebrin shows it to be 
capable of producing methaemoglobin, and we can rest 
assured that, while phenacetine is harmless in its influence 
on the blood in ordinary quantities, in very large toxic 
doses it acts destructively upon this tissue of the body. 

Nervous System. — The only studies of the physio- 
logical action of phenacetine upon the nervous system 
of animals with which the w r riter is acquainted are those 
which he has performed himself, an example of which 
here follows : — 

Frog ; weight, 3 ounces. 
10.45. Gave 1 grain of phenacetine into posterior 
lymph-sac. 



116 Fever : its Pathology and Treatment. 

10.50. Became quiet and somnolent. Moved slowly on 
irritation. Reflexes somewhat heightened in 
activity. 
10.52. Reflexes are decreased. Blood is dark and 
venous-looking. Skin on inside of thighs is 
discolored. Animal breathing very faintly. 
10.58. Dead from respiratory failure. The heart gives 
sometimes an abortive beat. 
In order to determine the cause of the loss of reflex 
action noted in this and similar experiments, other 
frogs were now given doses of the same size, the artery 
of the left leg being tied to protect that member. The 
same symptoms ensued as before, and the protected leg 
seemed as much affected as the unprotected limb, point- 
ing to the spinal cord as the part affected. This was 
further confirmed hy the injection of a small amount of 
the drug into the leg of the frog, the blood-vessels being 
tied. It was then found that this limb responded as 
well to stimulus as the other, proving that the nerve- 
trunks were unaffected, and that the failure of reflex 
activit} 7 must be spinal in origin. 

The increase of reflex activit} 7 noticed at first de- 
pends solely upon an indirect action of the drug upon 
the cord, and not upon a direct effect ; that is to say, the 
primar} 7 increase of reflex activity is due to the changes 
in the blood, and not to an effect directly exercised upon 
the nervous protoplasm. That the sensory side of the 
spinal cord is more affected than the motor, is proved 
by clinical as well as experimental observation. 

Urine and Elimination. — When as much as 45 
grains of phenacetine are given to a dog the urine be- 
comes strongly } T ellow, but not particularly dark ; and it 
has been found b} T Hinsberg and Kast that chloride of 
barium shows no sulphuric acid, but that boiling w T ith 




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Phenacetine : Experimental Evidence. 11T 

hydrochloric acid gives a copious precipitate of salts, 
which, accordingly, must exist exclusively in paired con- 
ditions or combinations. Copper oxide, when added to 
such urine, is reduced by prolonged boiling, and it has 
also been found that the urine rotates light half a degree 
to the left. 

Miiller 1 asserts that the addition of a solution of 
perchloride of iron produces with such urine a reddish- 
violet hue. 

The use of phenacetine in man, however, seems to 
cause a dark-yellow color of the urine, and the in do- 
phenol reaction can readily be obtained after 9 grains of 
the drug are given. 

A very important point, from a clinical stand-point, 
is the fact that this urine often gives the reaction for 
sugar with Fehling's solution, and for this reason the 
physician should be on his guard, lest he be led into a 
mistaken diagnosis of diabetes. 

Toxic Effect. — The toxic effect of phenacetine is 
only produced when very large amounts are used. 

Dujardin-Beaumetz 2 states that he has given as much 
as 37^ grains to a rabbit of 5 pounds without any toxic 
effect, and Misrachi and Rifal 3 also gave to a chicken 
18 grains without any signs of poisoning. They have 
also given 30 grains to animals for every 2 pounds of 
body-weight without bad effects. 

Conclusions as to Physiological Action of Phen- 
acetine. — 1. Phenacetine lowers normal temperature, 
and in fever lowers the pyrexia by decreasing the pro- 
duction and dissipation of heat. 

2. Upon the heart and circulation the drug has a very 
slight influence. 

1 Berliner klin. Wochenschrift, No. 30, p. 613. 

2 British Medical Journal, Marcn 9, 1889. 
s BuU. Ge'n. de The'rap., June, 1888. 



118 Fever: its Pathology and Treatment. 

3. Enormous toxic doses cause the blood to become 
dark and grumous, and change the haemoglobin into 
methsemoglobin. 

4. On the nervous system the drug exerts a distinct 
quieting influence by depressing the spinal cord, par- 
ticularly on its sensory side. 

5. The urine may become dark yellow under its 
influence, and cause a reaction with Fehling's solution. 

6. How the drug is eliminated we do not know. 

Clinical Evidence. 

Our knowledge concerning the influence of phen- 
acetine upon the human body in disease may be divided 
into two separate parts, in much the same manner that 
we divided the discussion of antipyrin, namely, its use 
as an antipyretic and as an analgesic. 

Like the other members of the antipyretic group 
which are blessed with this double action, the antipy- 
retic influences of phenacetine were first observed, and 
will, therefore, be spoken of before its analgesic powers 
are considered. 

The employment of this drug in medicine was first 
attempted by Hinsberg and Kast, 1 who, from the begin- 
ning, spoke of it in the highest terms of praise. They 
found that it seldom, if ever, caused serious untoward 
effects, and that its power over fever in the dose of from 
3 to 8 grains was quite extraordinary. Very shortly 
after the paper of these writers appeared, Kobler 2 pub- 
lished the report of its use in some 50 cases in the clinic 
of Bamberger, of Vienna, the febrile affections being 
tuberculosis, pneumonia, t} r phoid fever, pleurisy, and 
several other diseases of like character. He found, as 

1 Centralblatt fur die Wissenschaften, No. 9, 1887. 
3 Wiener Med. Wochenschrif t, 1887 ; or Centralblatt fur die Gesammte 
Therapie, August, 1887. 



Phenacetine: Clinical Evidence. 119 

have most of his successors, that the fall of fever does 
not occur for nearly half an hour after the dose is taken, 
and continues for from four to eight hours afterward. 

As a general rule, sweating was not noted as being 
present to any great extent, but in phthisis and advanced 
typhoid fever there can be no doubt but that chilliness 
and subnormal temperature may be caused. Cyanosis 
and vomiting did not occur in a single one of Kobler 's 
cases. In a very instructive case of pneumonia, due to 
septic infection in a patient of 20 years, phenacetine not 
only lowered the fever, but, in addition, decreased, to a 
large extent, the blood in the urine, and did not, in the 
slightest degree, influence the kidneys unfavorably. 
That the drug has power is evidenced by the fact that 
Kobler used it only when the temperature rose as 
high as 103°, 104°, or 105° F., and in these cases the 
temperature fell not less than from 3 to 5 degrees. 

It is very important to remember that morning doses 
of phenacetine seldom have as powerful an influence as 
evening doses. Two morning doses are only equal to 
one evening dose in most cases, and it is generally found 
better in phthisis to give the drug about noon, to pre- 
vent the evening exacerbation of temperature than to 
resort to it at a time nearer the p}^rexial period. These 
conclusions of Kobler have been confirmed by Heppe 1 
in a long series of studies, and the latter also points 
out the deleterious excess of ap} r rexia which sometimes 
comes on in debilitated cases of phthisis which take the 
drug. 

One of the advantages of having several drugs be- 
longing to one class is the benefit often derived from the 
use of one where another has failed. Thus, Huber 2 

1 Tlierapeutische Monatshefte, April, 1888. 

9 Correspondenzblatt fur Schweizer Aerzt, No. 18, 1888. 



120 Fever : its Pathology and Treatment. 

found that in several instances phenacetine was successful 
where antipyrin had not acted, and believes it to be the 
more powerful drug of the two, — a conclusion also 
reached by Heusner, 1 who thinks that 15 grains of 
phenacetine are equal to half as much antifebrin and to 
30 grains of antipyrin. Lepine, 2 who has done so much 
with the other antipyretics, also believes it to be su- 
perior to them all, and in this Guttmann 3 is largely of 
the same opinion. Similar results to those so far 
named have also been reached by Gueorguievski, 4 Mis- 
rachi and Rifal, 5 Suckling, 6 Mays, 7 Roe, 8 and Rumpf, 9 
as well as Greenfell, 10 Miiller, 11 Zannas, 12 Perera, 
Fesce, 13 and Cesari and Burrani. 14 

One of the most thorough and careful studies, other 
than those which have been named, is that of Cattani, 15 
of Milan, who has used phenacetine in over 50 cases of 
all kinds, and whose conclusions are well worth reading. 
He found that not only does phenacetine readily reduce 
pyrexia, but also that it acts more favorably when the 
fever is high than when it is low, and that the arrival 
of the temperature at the normal is not accompanied 
by the evil after-effects so often observed with other 
antipyretics. 

1 Therapeutische Monatshefte, p. 103, 1888. 
9 La Seinaine Medicale, December 21, 1887. 

3 Deutsche Medicinal-Zeitung, July 12, 1888. 

4 Bulletin Gen. de The'rapeutique, May 30, 1888. 
"Ibid., June 15, 1888. 

6 British Med. Journal, April 28, 1888. 

7 Medical News, August 20, 1887. 

8 British Medical Journal, May 26, 1888. 

9 Berliner klin. Wochenschrift, June 4, 1888. 

10 Practitioner, May, 1888. 

11 Therapeutisehe Monatshefte, August, 1888. 

12 Gazette Me'd. de 1' Orient, June 30 1888. 
" Le Bulletin Me'dicale, May 30, 1888. 

14 Bulletin Gen. de The'rapeutique, June 15, 1888. 

15 Gazetta Medica Italiana Loinbardia, 1888, Nos. 39 to 48. 



Phenacetine : Clinical Evidence. 121 

Faulkner, 1 of the Bombay Army, has studied 
phenacetine, and he finds in most instances that its 
action is most favorable in the pyrexia of malarial 
affections. He concludes that in phenacetine we have 
a most useful medicine in the treatment of cases so 
commonly seen in India and other tropical countries, 
namely, those intermittent and continuous fevers which 
sometimes act with surprising rapidity and violence 
both as to their temperature and systemic influence. 
He thinks that though phenacetine does not always act 
in proportion to its dose, no disagreeable effects follow 
its employment whatever, even though larger doses than 
necessary are used. Rohden 2 has come to a similar 
opinion, but Warfringe 3 has denied the correctness of 
this belief. It has also been found that in typhoid fever, 
while the drug does not cure, it successfully combats 
the fever, diminishes the headache, and clears the mind. 
In croupous pneumonia the drug lowers the fever, but 
does not alter the course of the disease, although it 
diminishes the pain and relieves the dyspnoea. 

The conclusions which the writer has reached are 
identical with those named above. He has found the 
drug to be possessed of powerful antipyretic influence, 
and to be useful in nearly all the fevers in which anti- 
pyrin can be employed. At the same time, he does not 
look upon it with the same degree of confidence that he 
does the older drug, when he is anxious to relieve a 
fever which seems dangerous and worthy of rapid and 
certain reduction. 

Nervous System. — Among those who have found 
phenacetine of value in the treatment of pain may be 

1 Indian Medical Gazette, August, 1889. 
9 Deutsche Medicin. Wochenschrift, May 3, 1888. 
3 Hygeia, Stockholm, August, 1888. 
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Temperature Chart showing that Antipyrin is More 
Powerful in Reducing Fever than Phenacetine. 



(123) 



124 Fever : its Pathology and Treatment. 

named Ott, 1 Muller, 2 Heppe, 3 Hottenstein, 4 Pesce, 5 Ce- 
sari and Burrani, 6 Guttmann, 7 Michaelis, 8 Gueorguiev- 
ski, 9 Rurnpf, 10 Heusner, 11 Zadok and Nessim, 12 Mis- 
rachi and Rifat, 13 Dujardin-Beaumetz, 14 Preston, 15 
Rabuski, 16 Cattani, 17 and Gaitfe. 18 

As an antineuralgic, in migraine and in ordinary 
headache from eyes train, in tabes dorsalis, in intercostal 
neuralgia, and in rheumatism, phenacetine undoubtedly 
brings relief very rapidly, and does so even when anti- 
pyrin has failed. In the acme of whooping-cough 
Michaelis has seen it take the place of antipyrin. 
Indeed, it would seem as if the drug rivaled antipyrin 
in its nervous influences. 

Gaiffe found it relieved the pain of gastralgia and 
did good in nervous polyuria. Thus, in a case of the 
latter disease, the excretion of urine fell under phen- 
acetine from 215 ounces to 140 ounces per day. 

The following words of Dujardin-Beaumetz seem 
worth repeating here without any excuse being made 
for their interpolation, and, coming from such a dis- 
tinguished French writer, are worthy of consideration. 

1 Prager Medicin. Woclienschrift, October 3, 1888. 

2 Therapeutische Monatshef te, August, 1888. 

3 26m*., April, 1888. 

4 University Medical Magazine, January, 1889. 

8 Le Bulletin Medicate, May 30, 1888. 

6 Bull. Generate de Therapeutique, June 15, 1888. 

7 Deutsche Medicinal-Zeitung, July 12, 1888. 
• Ibid. 

9 Bull. Ge'n. de The'rap., May 30, 1888. 

10 Berliner klin. "Woclienschrift, June 4, 1888. 

11 Therapeutische Monatshef te, p. 103. 1888. 

12 Gazette Me'd. de 1' Orient, June 30, 1888. 

13 Bull. Ge'n. de Therapeutique, June 15, 1888. 

14 British Medical Journal, March 9, 1889. 

15 American Medical Digest, April 15, 1889. 

16 Deutsche Med. Wochenscriffc, No. 37, 1888. 

17 Gazetta Medica Italiana Lombardia, 1888, No. 39. 

18 Bulletin Generate de Therapeutique, 1888, p. 71. 



Phenacetine: Clinical Evidence. 125 

" But it is above all as an analgesic that phenacetine 
outrivals its predecessors. While it is quite as power- 
ful as antipyrin and acetanilid, it does not cause the 
pain in the stomach, or the scarlatiniform rash of the 
former ; nor does it give rise to the cyanosis of the 
latter. However prolonged may be its administration, — 
and I have given it for months in doses of 1 to 2 
grammes (15 to 30 grains) per day, — I have never ob- 
served any bad effect. I have used it for the relief of 
every form of pain (neuralgias, migraine, rheumatic 
pains, muscular rheumatism, acute articular rheuma- 
tism, the lightning pains of tabes, etc.), and always with 
the best results. Further, in cases of hysteria, and of 
hysterical or neurotic pains, phenacetine has seemed 
to produce better effects than the bromides ; it calms 
the excitability of the nervous system, and in some 
obstinate cases of nervous insomnia it produced sleep. 
Phenacetine seems, therefore, to be not only an analgesic, 
but a narcotic." 

The results of the writer's trials of phenacetine in 
the wards of the St. Agnes Hospital are entirely confirm- 
atory of these opinions, except in so far as any narcotic 
effects are concerned. 

The two following cases illustrate the activity of the 
drug in relieving pain : — 

Case 1. — A. O., aged 48 years; laborer. Suffers 
from chronic myelitis and much pain about small of 
back. Sometimes has " girdle-pains " of a severe char- 
acter, which last for a week at a time. 

Ordered 4 grains of phenacetine three times a da} r , 
with an almost complete relief from the pain. Anti- 
pyrin did no better, but as well, for him. 

Case 2. — B. E., male; laborer; also suffering from 
chronic myelitis, with pain in the lumbar region and 



126 Fever : its Pathology and Treatment. 

" girdle-pains. " Two grains three times a day relieved 
him completely, and the dose was first reduced to twice 
a day, and then to one dose at night. Of course, the 
progress of the disease was not checked. 



SALICYLIC ACID AND ITS COMPOUNDS. 

Originally introduced into medicine for the purpose 
of acting as an antipyretic, salicylic acid is rarely em- 
ployed for that purpose to-day, being almost solely used 
for its antirheumatic power. That the drug does 
possess antipyretic influences to some extent has been 
proved over and over again, but it has also been found 
that, compared with the newer antipyretics, it is very 
weak. 

While the propriety of considering the drug as an 
antipyretic may be questioned, the writer has done so 
because it seems best to include the good and the bad, 
in order that the distinction may be the more marked. 

Experimental Evidence. 

General Effects. — When salicylic acid is given in 
sufficient dose to a normal man it produces a con- 
dition of ringing in the ears closely resembling that 
caused by large doses of quinine. If this symptom 
is not present it may be replaced by buzzing or bell- 
like sounds, or loud reports quickly following each 
other. The face may be somewhat flushed and the eyes 
slightly blood-shot. If the dose used be still larger, these 
symptoms are naturally much increased. The ringing 
in the ears goes on to total deafness and dimness of 
vision ; amblyopia of a complete type and profuse 
sweating and exhaustion may assert themselves, and 
the temperature of the body is usually subnormal. 

The symptoms just detailed are those of large, non- 
toxic doses, and do not include those seen in truly 
poisoned patients. In this class the amblyopia is fol- 

(127) 



128 Fever: its Pathology and Treatment. 

lowed by ptosis, more or less marked, by wild, inco- 
herent delirium, of either a melancholic or cheerful type, 
and by irregular respiratory movements. By and by, 
the delirium becomes more quiet and the patient or 
animal slips gradually into a coma, from which nothing 
can arouse him. The pulse is now slow and weak, or 
fluttering in its powerlessness, the urine is passed, 
along with the faeces, involuntarily, and is of a peculiar, 
greenish hue, pathognomonic of the presence of the 
drug. The cause of this color will be spoken of later on. 
In dogs death ensues amid convulsions and dyspnoea, the 
fatal result being brought about by failure of respiration. 
Heat Functions. — The administration of salicylic 
acid to an animal having a normal temperature nearly 
alwaj^s has the effect of lowering the heat of the body 
a fraction of a degree at least. Not only has the writer 
found this to be the case in man, but in animals also, 
and in this he is confirmed by a large number of other 
investigators both in this country and abroad. 

The following experiment represents fairly well the 
results reached by me in several experiments on rabbits. 
Experiment. — Rabbit ; weight, 3 kilos ; gv&y ; full 
grown. 

10.35. Rectal temperature, ..... 102.5 
10.40. Gave hypodermic ally 2 grains of salicylic acid. 

10.45. Rectal temperature, 102.5 

10.50. " " 102.4 

10.55. " " 102.25 

11.05. " " 102.1 

11.15. " " 101.8 

11.25. " " ..... 101.3 

11.35. " " 101.3 

Confirmatory of these experiments are those of 
Gedl, 1 North, 2 Chirone and Petrucci, 3 all of whom 

1 Centralblatt fur die Med. Wissenschaften, 1876, p. 403. 

2 Practitioner, xxiii, 181. 

8 Coininentario Clinica di Pisa, January and February, 1878. 



Salicylic Acid: Experimental Evidence. 129 

state that moderate doses of salicylic acid lower normal 
bodily temperature. It is true that in Gedl's experi- 
ments upon man the result was not constant in every 
case, but the changes noted by North were very marked 
indeed, for he found that the drug absolutely prevented 
the rise of bodily heat usually consequent upon severe 
muscular effort. The experiments of the writer were 
all performed on rabbits in perfect health to the number 
of five, and showed a constant fall of temperature 
amounting to a fraction of a degree or more. Using 
dogs and rabbits, Chirone and Petrucci also found such 
a fall to occur. 

The effect of larger, almost toxic, doses of the drug 
upon temperature in health is not constant, and it is this 
w r hich has given rise to the assertions made by some 
writers that the temperature was not depressed by sali- 
cylic acid, but even raised. That these statements are 
based upon accurate observation cannot be gainsaid, but 
it will be found on examination of the papers that the 
doses employed by all were not the same. Chirone and 
Petrucci recognize this fact, and state that poisonous 
amounts may raise the bodily heat rather than lower it, 
and in this they are confirmed by the results of Germain 
See, 1 who found that as much as 150 grains had little if 
any depressing effect. Aside from this, it is but fair to 
state that D anew ski found the action of ordinary 
amounts identical in the dog and man, and that Fur- 
bringer, 2 in a similar line of investigation, reached cor- 
responding results. In view of the studies of the 
writer, whose animals were free to run about, and, in 
view of those of Gedl and North, it is justifiable to 
reach the conclusion that, while the action of salicylic 

1 Bulletin de l'Academie de Medecin, June, 1877. 
a Centralblatt fur die Med. Wissenschaften, November 18, 1875. 
6* 



130 Fever: its Pathology and Treatment. 

acid on normal temperature is not always constant, the 
tendenc} r of small doses is to act as a depressant. 

The manner in which this fall occurs is not posi- 
tively known, and is difficult of discovery owing to the 
small variation produced ; but the writer, in a series of 
studies, came to the conclusion that it resulted from 
decreased heat production and dissipation. He be- 
lieves, however, that this conclusion is not to be taken 
as entirely correct, since his results hardly support his 
deductions, owing to the slight fall which ensued after 
the doses which were used. 

Upon the fevered animal the drug always tends to 
act as an antipyretic, as has been proved a great 
number of times by clinicians and experimenters. 
Thus, Furbringer produced septic fever in rabbits, and 
found in 9 cases a distinct lowering of the temperature 
after the administration of the drug, the dose varying 
from | to 3 grains. The fall occurred in from four to 
six hours after the drug was given. The same results 
were also reached by him in the case of two rabbits who 
were fevered b>^ a pyaemia due to the injection of pus 
under their skin. On other animals who were fevered 
by inunctions of croton-oil the drug had little effect. 

The writer has found, however, that small doses have 
no influence over the fever produced in dogs by the in- 
jection of pepsin, probably because his doses were too 
small. His calorimetrical experiments on this question 
are of little value owing to this fact, but, so far as he 
can judge, the fall is due to diminished heat production 
and dissipation. 

Zimmermann 1 found, in some experiments on rabbits 

carried out in the Pharmacological Institute of Greifs- 

wald, in which fever had been produced by the injec- 
1 Archiv fur Experimental Pharm. und Pathologie, 1875, p. 248. 



Salicylic Acid: Experimental Evidence. 131 

tion of putrid substances, that salicylic acid, given by 
the mouth or subcutaneously, produced virtually no 
antipyretic effect. 

Circulation. — Our knowledge of the influence of 
salicylic acid on the circulation has been in the past 
confused and uncertain, and the writer has, therefore, 
thought it well to perform a number of experiments in 
regard to these points, the results of which may be seen 
in the following tracings (pages 132a to lB2d). 

From these it would appear that in moderate amount 
the drug does not depress the pulse-rate or arterial 
pressure, but if, by chance, it comes in contact with the 
heart in large amounts or very suddenly, it depresses 
that viscus. This is confirmed by the assertion of Chi- 
ron e and Petrucci, namely, that in the frog the heart- 
beats are diminished somewhat, while in the mammal 
they may be unchanged, or slowed, or accelerated. 

Further than this, Oltremare 1 has found that the 
drug increases the arterial pressure and pulse-force, as 
has also Danewski. 2 The rise of pressure noted by 
them was due to stimulation of the heart and vasomotor 
centre, for the rise did not occur if previous section was 
made of the spinal cord. The author has confirmed 
these studies, as may be well seen in the tracings. 

When a dose amounting to 2 grains is injected into 
the jugular vein of a dog of 21 pounds, there is a fall 
in pressure and pulse-rate of a very marked degree. 
This has been confirmed by Kobler, 3 and also by Oltre- 
mare and Danewski, who have found that the action is 
exerted directly upon the heart. 

Although tracings taken from the surface of a blood- 

1 These de Paris, 1889. 

3 Arbeiten d. Pharmacol. Laborat. Moskau, i, 190. 

8 Centralblatt fur die Med. Wissen., 1876, pp. 163, 195. 



132 Fever: its Pathology and Treatment. 

vessel can be made to show almost anything, and are, 
therefore, not of much value, it is proper to notice here 
the studies of Maragliano 1 with the sphygmograph, 
who also used the sphygmomanometer of Basch upon 
patients under salicylic acid. He asserts that his 
results showed a rise of blood-pressure and pulse-force 
whenever the drug was used in moderate quantity. 

Tissue Waste or Bodily Metabolism. — The knowl- 
edge which we possess in regard to the influence of sali- 
cylic acid or its compounds upon the tissues of the 
body is, to say the least, meagre. The most reliable 
information is that of Wolfsohn, 2 who has found that 
under its influence the nitrogenous elimination is con- 
siderably decreased. On the other hand, Germain See 3 
states that in gout the uric acid thrown off by the body 
is very greatly increased and the quantity of urea 
remains unaffected, — a result which, if correct, is, to say 
the least, curious and inexplicable. 

The studies of Lecorche and Salamon upon patients 
suffering from rheumatism show a primary increase 
of great extent in the excretion of urea and uric 
acid, followed by a diminution which, in its fall, may 
pass below the line maintained before the drug was 
used. Thus, they found that in acute rheumatism the 
increase lasted three or four days ; in subacute rheuma- 
tism one or two days, with an excretion of phosphoric 
acid, which was at first increased, then lessened. These 
results have also been largely confirmed by Carl Vir- 
chow, 4 who, in using dogs, found the nitrogenous elimi- 
nation increased by salicylate of sodium. 

1 Zeitsclirift fur klin. Med., 1884, viii, p. 248. 

3 Inaugural Dissertation quoted in Centralblatt fur Medicinische 
Wissenschaften, 1877, p. 30. 

3 Bulletin de l'Academie de Medecin, 1877, p. G97. 

4 Zeitsclirift fur Physiologische Chemie, vi, p. 78. 




132a 




Same Continued. 




Same Continued. Two Grains more Given, which Caused 
Death. 




Same Continued, showing Approach of Death. 
132c 




132d. 



Salicylic Acid: Experimental Evidence. 133 

Nervous System. — That salicylic acid has quite a 
distinct influence over the nervous sj r stem cannot be 
denied, but that this influence in any way affects its value 
in fever or rheumatism is very doubtful. In the lower ani- 
mals, after poisonous doses, violent clonic and tonic con- 
vulsions ensue, arising, apparently, both from the brain 
and spinal cord. The action on the nerve-trunks, both 
sensory and motor, seems to amount to nothing, and, 
unless the doses are quite toxic, no change in reflex 
action is apparent. 

Laborde, 1 from studies on the dog, affirms that only 
the centres in the perceptive portions of the brain are 
affected, but admits that some of the spinal cells may 
also be depressed, and in this he is confirmed by the 
studies of Bochefontaine, 2 who found in frogs that the 
drug acted as a paratyzant of the spinal cord. It is at 
once evident that the convulsions witnessed by See are 
produced by larger amounts of the drug than caused 
the paralysis seen by Bochefontaine and Laborde ; in 
other words, the coma of advanced poisoning was at 
such a time asserting itself, but yet enough of the drug 
had not been given to produce convulsive seizures. 
Laborde gave as much as 60 grains to a dog, and found 
cutaneous ansesthesia very well marked, but if he had 
given 120 grains he would subsequently, in all proba- 
bility, have obtained a convulsive attack. 

Respiration. — Here, again, most of our knowledge 
is derived from the studies of Kobler 3 and Danewski. 4 
The first of these investigators noted that the drug, 
when injected into the jugular vein, caused a primary 
quickening of the respiratory movements, followed by 

1 Bulletin de Therapeutique, xciii, p. 276. 

2 Le Progres Medieale, 1877, p. 630. 

3 Centralblatt fur die Med. Wissenschaften, 1876, p. 163. 
* Arbeiten d. Pharm. Labor at. Moskau, i, p. 190. 



134 Fever: its Pathology and Treatment. 

a slowing which placed them below the normal rate. 
These conclusions have also been found correct by 
Danewski, who, with Kobler, found that section of the 
vagus nerves during the time the respirations were 
slowed caused a still further reduction in respiratory 
rate. 

Danewski found, too, that if the vagus nerves were 
cut before any drug w T as given, the primary acceleration 
was almost absent. He concludes that the respiratory 
changes are reflex in character and dependent upon irri- 
tation of the terminal afferent filaments of the nerve in 
the pulmonary tissues. As to whether the drug affects 
the respiratory centre directly, we have no positive 
evidence. 

Of two things, however, there can be no doubt : first, 
that even very large medicinal doses only affect the 
respiration but slightly, if at all ; and, second, that poi- 
sonous doses in sufficient amount to kill do so by de- 
pression of the respiratory centre. 

Absorption and Elimination. — Salicylic acid is ab- 
sorbed very rapidly, indeed, \>y the body, whether it be 
in anj r of its combined salts or not. Not only is this 
true, but it is taken up with great rapidity by the skin 
and mucous membranes, and may even be administered 
to patients by applications to such surfaces. The writer 
has treated acute articular rheumatism on several occa- 
sions, when the stomach was disturbed, b} 7 inunctions 
of the acid rubbed up with vaseline ; and Randolph has 
shown that the oil of gaultheria (salicylate of methyl) 
may be inhaled from a sponge and appear in the urine 
in a few minutes. The absorbability of the drug from 
the sound skin has also been tested and proved by 
Drasche. 1 

1 Centralblatt fur Chirurgie, 1876, p. 777. 



Salicylic Acid : Experimental Evidence. 135 

Salicylic acid is so insoluble in ordinary menstrua 
that it is interesting to know how the digestive juices 
dissolve it, for, although they seem to possess great 
power as solvents, their action must be exceedingly 
rapid to enable the drug to appear in the urine so soon 
after its ingestion. At the present time, however, 
there exists little doubt but that salicylic acid is ab- 
sorbed as such, and at once transformed into salicylate 
of sodium upon its entrance into the blood. This 
thought is not only confirmed by logical reasoning, but 
by the results reached by Salkowski, 1 which were of an 
identical character in their conclusions. Whatever of 
the acid escapes into the intestines probably is changed 
into a salt before it is absorbed by the alkaline juices 
there present. 

Though this is the theory now most generally ac- 
cepted, it is by no means that which has been universally 
received in the past. Very early in the study of the 
drug, Binz, 2 of Bonn, brought forth the theory that the 
acid is liberated in the blood by the carbonic acid there 
found, but his reasons for this belief are so poorly sub- 
stantiated that they do not deserve more than a passing 
mention. He found that if carbonic-acid gas is passed 
through a solution of phosphate, carbonate, or salicy- 
late of sodium, which is then agitated with ether and 
evaporated to dryness, ciystals of salicylic acid appear. 
As has already been pointed out elsewhere, the same 
result ought to be obtained if the blood of an animal, 
poisoned by salicylic acid, be shaken with ether ; but 
this is not so. Thus, Feser and Friedeberger found 
that only enormous (instantaneously) lethal doses would 
give such a result. Again, in a series of studies by 

1 Berliner klin. Wochenschrift, 1876, p. 297. 
a London Practitioner, xxvi, 443. 



136 Fever: its Pathology and Treatment. 

Kobler, 1 upon this same point, it was found that no acid 
was yielded when poisoned blood was shaken with ether, 
unless that blood was venous in character, when, owing 
to the carbonic acid present, acid was yielded. It would 
seem probable, therefore, that the salicylic acid is not 
held, as is the case with quinine, in solution by the 
gases of the blood, but, by reason of its change in 
chemical form. 

Feser and Friedeberger believe that the drug is held 
in solution as an albuminate, and Farsky 2 has confirmed 
this idea to some extent ; at least, he succeeded in prov- 
ing that the acid will form such a combination. This 
has been denied by Fleischer, 3 and, in consequence, the 
question as to this minor point is as yet undecided. 

The studies which have been devoted to the deter- 
mination of the manner of elimination of the acid, when 
once it is absorbed, have brought results at once more 
interesting and fruitful of general agreement. During 
the time that the question of the mode of absorption was 
worrying the minds of the physiological chemists, Fur- 
bringer and Drasche 4 found no trace of the acid in the 
faeces, saliva, bronchial secretion, or the sweat. Their 
conclusions have, however, been contradicted, probably 
correctly, by Mussy 5 and by Balz, 6 both of whom found 
the drug in the saliva. Outmont also found it in the 
serum of a blister. 

It has been found that elimination by the urine is 
very rapid indeed, occupying onty a few minutes, and the 
writer has confirmed the results of others on this point 

1 Loc. cit. 

2 Sitzb. d. k. Akad. d. Wissens., lxxiy, Bd. ii. 
* Medic. Centralblatt, 1876, p. 628. 

4 Centralblatt fur Chirurgie, 1876, p. 777. 
6 Bulletin Gen. de Therap., xiii, p. 318. 
6 Archiv fur Heilkunde, xviii, p. 60. 



Salicylic Acid: Experimental Evidence. 137 

many times. Balz records an interesting case of 
exstrophy of the bladder, in which salicylieized urine 
was detected dripping from the ureters within 8^ min- 
utes after the ingestion of the drug. Byanow 1 has 
recovered it from the urine in twenty-five minutes, and 
Ewald has seen similar cases. Any one can easily make 
studies upon himself by taking the drug and shortly 
afterward adding a few drops of a solution of the 
chloride of iron to his urine, when a purple hue will 
appear if salicyluric acid is present. 

Aside from the rapidity of elimination we must ex- 
amine as to the form of the drug when it escapes. 

Bjanow found it altered into salicyluric acid and 
salicin, and to a slight degree into oxalic acid. Stuart 
asserts that he has seen c^stals of salicyluric acid in 
the urine even after small doses of the drug. 

Whenever salicylic acid or one of its compounds is 
given in excess, the urine becomes olive-green in hue. 
This is said to be due to the presence of a chemical 
compound formed, not from the acid, but from its 
action with the juices and contents of the intestines. 
Aolfberg 2 and Robin 3 insist that this substance is indi- 
can, or pyrocatechin, 4 or that both compounds are 
present. 

Antiseptic Action. — The antiseptic power of salicy- 
lic acid far exceeds that of most other antipj^retics, yet 
it by no means holds a place equal to the drugs com- 
monly used for such purposes. Acting in a much 
milder manner than carbolic acid or corrosive subli- 
mate, it prepares so poor a field for the growth of micro- 



1 Centralblatt fur Chirurgie, 1877, p. 809. 

a Deutsche Archiv fur klin. Med., xv, p. 403. 

8 London Med. Record, 1877, p. 151. 

* Bulletin de l'Acad. de Med., 1877, p. 507. 



138 Fever : its Pathology and Treatment. 

organisms that they fail to multiply. Its power is 
antiseptic, while the influence of the others is germicidal. 

Aside from the abundant clinical proof which we 
possess, a large number of experimental studies, sur- 
rounded by all the accuracy of the laboratory, have 
been carried out. Very early in its use in medicine 
Kolbe found that four-hand redths of a 1-per-cent. solu- 
tion prevented milk from souring to a very great extent, 
while Bucholz 1 has asserted that fifteen-hundreths of 
1 per cent, will prevent the development of bacteria in 
ordinary organic mixtures. He also found so small a 
quanta as 0.005 per cent, to possess distinct power, 
while 0.3 per cent, killed bacteria which were previously 
in a flourishing state. Experiments on the salicylate of 
sodium showed it to be of almost equal value. Pri- 
deaux 2 has confirmed these results in a very practical 
manner in regard to urine, finding that \ grain to the 1000 
of urine keeps such a liquid clear for fourteen days, al- 
though very inactive bacteria can be seen in three days. 
One grain per thousand almost entirely inhibits any 
change, and 1^- grains render the urine capable of being 
kept indefinite! j\ He also found, what many others 
have noted, that the urine of patients taking this drug 
remains sweet for a long time. A rather curious fact is 
that the addition of 3 or 4 grains of salicylic acid to 
putrid urine kills all the bacteria, but does not in the least 
destroy the characteristic odor. Similar conclusions 
to those of Prideaux have been reached by Meyer and 
Kolbe, 3 and many others. 

Further than this, Miller and Kolbe have found it to 
prevent the action of emuisin and amygdalin, so inhib- 



1 Arch, fur Experimental Path, und Pharm., Bd. iv. 
3 London Practitioner, September, 1878, p. 177. 
a Journal fur Prakt. Chemie, Bd. xii. 



Salicylic Acid: Clinical Evidence. 139 

iting the development of hydroc3 T anic acid. Miller also 
found the proteolytic ferment of pepsin seriously re- 
tarded in its action by the drug. 

Conclusions as to the Physiological Action of 
Salicylic Acid and its Compounds. — Salicylic acid 
lowers normal bodily heat very slightly, but nevertheless 
seems to possess some such influence. 

In fever it acts as a more or less powerful antipyretic 
according to its dose, the cause of the fever and its height. 

On the circulation the drug has little effect in ordi- 
nary amounts, but if it comes closely in contact with 
the heart in concentrated form it acts as a paralyzant. 

While the evidence in regard to its influence over 
tissue waste is somewhat contradictory, it would seem 
probable that in health and disease the nitrogenous ex- 
cretion is increased, but afterward decreased. In very 
large poisonous doses it produces convulsions in the 
lower animals, preceded and accompanied by coma. 
The drug acts chiefly on the brain and spinal cord, not 
on the nerves and muscles. 

Ordinary amounts quicken the respiration very 
slightly ; larger ones kill by depression of the respira- 
tory centre. 

As an antiseptic it possesses very considerable power, 
but no germicidal influence. 

Clinical Evidence. 
That overdoses of salicylic acid are perfectly capa- 
ble of producing serious effects has already been pointed 
out, and on the following pages the writer has collected 
a list of cases reported by various writers where patients 
taking the drug either had bad symptoms produced by 
overdoses, or had such an idiosyncrasy as to be equally 
seriously affected : — 



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On onset of 
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stopped for 2 
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(151) 



152 Fever : its Pathology and Treatment. 

On looking over these tables we find that the follow- 
ing facts may be gleaned from them. 

In the first place it is evident that age has some pre- 
disposing effect, as may be seen from the following 
table : — 



Males 




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ltolO 


years, 


1 case. 


10 to 20 


(< 


11 cases. 


10 to 20 


n 


8 cases. 


20 to 30 


u 


10 cases. 


20 to 30 


n 


7 cases. 


30 to 40 


it 


5 cases. 


30 to 40 


cc 


5 cases. 


40 to 50 


u 


4 cases. 


40 to 50 


a 


2 cases. 


50 to 60 


a 


— cases. 


50 to 60 


u 


— cases. 


60 to 70 


a 


— cases. 


60 to 70 


a 


— cases. 


Adults, 


no age 




Adults, no age 




stated 


• • 


3 cases. 
34 cases. 


stated 


i 


5 cases. 
28 cases. 



It will be seen that the ages most commonly exhibit- 
ing untoward effects are from 10 to 40 years in both 
sexes, which is rather remarkable, since the old are so 
frequently rheumatic that one would expect to find cases 
between 50 and 70 years. 

That sex exercises little effect is seen very well in 
the columns just given, although the males seem to suffer 
a little more frequently than the females, probably be- 
cause males more frequently have rheumatism, owing to 
exposure. 

The size of the dose producing evil effects varied 
very greatly ; sometimes it amounted to saturation of 
the sj^stem by prolonged administration of large 
amounts. In others it followed after as little as 60 
grains in one dose. Mild untoward effects, of course, 
followed smaller amounts. 

The time of onset naturally varied with the mode of 
ingestion of the drug, and two classes may, therefore, 



Salicylic Acid: Clinical Evidence. 153 

be formed, those in which bad effects occurred after a 
single dose and those in which the effects came on after 
many large doses. In most of the former the s} T mptoms 
came on at once, while in the second series of cases the 
time varied too much to make it possible to draw 
conclusions. 

The s} r mptoms most commonly seen were collapse, 
profuse cold sweats, giddiness, headache, and delirium, 
especially at night. This last symptom, with headache, 
was more common than all the rest. 

No exact time of duration can be determined upon. 
In some cases the symptoms passed away at once on the 
withdrawal of the drug, in others they continued for 
days, or, in those cases where the lesions were serious, 
went on to death or a life of invalidism or chronic dis- 
ease, as in cases of retinal haemorrhages. 

The results, so far as recovery or death is concerned, 
are encouraging, — only 7 deaths in 59 cases. It is to be 
noted, however, that, unlike the deaths from the other 
antipyretics, where a serious disease, sufficiently severe 
to be capable of destroying life was present, in these 
cases the drug seems to have been largely, if not en- 
tirely, responsible for the fatal effect. On the other 
hand, it must be remembered that, as a rule, the doses 
given to these cases were very large, and the drug con- 
tinued after signals of distress had been displayed to a 
sufficient degree to make it proper to discontinue the 
medicament at once. 

The temperament and occupation of the cases re- 
corded are not eligible for study, owing to faulty 
reports. 

The diseases in which untoward effects manifested 
themselves were as follow : — 



7* 



154 Fever: its Pathology and Treatment. 



Acute articular rheumatism 


, 48 


Ophthalmia, 1 


" Rheumatism ," . 


. 7 


Erysipelas, 1 


Diabetes, 


4 


Nephritis, 1 


Fever, .... 


2 


Vaginal discharge, . . 1 


Chronic rheumatism, . 


1 


Phthisis, 1 


Marasmus, . 


1 


Typhoid fever, ... 1 


Pleurisy, 


1 





Acute rheumatic cases are the most frequent chiefly 
because of the common employment of the drug in 
this disease, although it would seem probable that 
the alterations in the blood produced by the rheumatic 
poison may have had some effect, combined with the 
action of the drug. 

A very interesting review of a number of these 
cases has been contributed by Shaw, in Guy's Hospital 
Reports for 1886-87, the patients having been inmates 
of this institution. 

The following table gives the statistics of the cases 
for 1881 and 1886 :— 

1886. 1881. 

No toxic effects mentioned, .... 23 40 

Toxic effects, 49 62 

Delirium, 12 21 

Deafness, 28 33 

Vomiting, 17 15 

Tinnitus, .... . . 13 16 

Headache, 21 12 

Epistaxis, 5 6 

Irregular or slow pulse, .... 9 4 

Albuminuria, 2 4 

Hematuria, 1 1 

Retinal haemorrhage, — 1 

Urticaria, — 1 

There is one point to be remembered in relation to 
these cases of untoward symptoms. In a very large 
number of them the drug used was out of all propor- 
tion to the effect desired, and in some cases the dose 



Salicylic Acid: Clinical Evidence. 155 

was pushed beyond the boundary of the medicinal into 
that of the poisonous. 

The clinical evidence of the value of salicylic acid 
may be divided into three parts, namely, as an antipy- 
retic, as an antiseptic, and as an antirheumatic. The 
first of these divisions naturally, in this instance, at- 
tracts us the most. 

The employment of salicylic acid as an antip} 7 retic 
was resorted to by Butt, 1 in 1875, and immediately after- 
ward a very large number of other clinicians hastened to 
record their observations upon it, among the first of 
whom may be mentioned Furbringer, 2 Senator, 3 Jahn, 4 
Nathan, 5 Riess, 6 Gottdammer, 7 Bertholet, 8 Weber, 9 
Steinitz, 10 and Buss, 11 as well as Hiller, 12 Pel, 13 Wag- 
ner, 14 Buch, 15 Schultz, 16 Molli, 17 Fischer, 18 and Wolf- 
berg. 19 This list of names by no means completes the 
bibliography of the short space of less than one year, 
but gives a fair idea of the immense number of papers 
given us immediately on the introduction of the acid as 
an antipyretic. 

1 Centralblatt fur die Medicin. Wissenschaft., No. 18, 1875. 

2 Ibid. 

3 Berliner Medicin. Gesselschaft, June 2, 1875. 
* Der Feldartz, No. 1, 1876. 

6 Deutsche Zeitschrift fur Prakt. Med., No. 2, 1876. 
6 Berliner klin. Wochenschrift, Nos. 50 and 51, 1875. 
1 Ibid., No. 4, 1876. 

8 Archiv fur Heilkunde, 2 und 3 Heft, 1876. 

9 Allgemeine Med. Central. Zeitung, March 25-29, 1876. 

10 Ibid.. Feb. 13, 1876. 

11 Deutsche Archiv fur klin. Med., Bd. xv, Heft 5 and 6. 

12 Ibid., xvi, 1875. 

13 Ibid., Bd. xvii, 1876. 

14 Journal fur Prakt. Chemie, Bd. ii, 1875. 

15 Allgemeine Med. Central. Zeitung, February 26, 1876. 

16 Ibid. February 16, 1876. 

" Berliner klin. Wochenschrift, No. 38, 1875. 

i 8 Deutsche Zeitschrift fur Prakt. Med., No. 13, 1875. 

18 Deutsche Arch. f. klin. Med., Bd. xvi. 



156 Fever: its Pathology and Treatment. 

Perhaps no better way of studying the subject can 
be found than to speak of the results of these clinicians 
collectively, reserving special mention for those whose 
papers deserve much recognition. 

Every observer who has used salicjdic acid must 
have noted a fall of temperature of a more or less 
marked form, and they have also noted that if the drug 
be at all cumulative in its action this fall may go on 
into a subnormal temperature, and even to collapse. 
Further than this, all clinicians are in accord with a 
statement made by the writer elsewhere, viz., that the 
antipyretic power of the drug depends very largely 
upon the disease, the dose, and the severity of the 
fever. 

Typhoid and Other Low Fevers. — In such fevers 
as these there can be no doubt but that salicylic acid 
no longer occupies a position of much importance, and, 
indeed, it may be said that its use is hardly to be 
thought of unless under most unusual circumstances. 
The reasons for this are several, but chief among them 
is the relaxation and collapse which we clinically observe 
after the use of the drug, and the fact that we have far 
more sure, active, and agreeable measures, equally con- 
venient for use. Further than this, the writer has 
found that salicylic acid either does not lower fever at 
all, or, if it does do so, acts very suddenly and with un- 
looked-for and undesirable power. Again, the general 
experience is that the acid often sweats the patient pro- 
fusely without lowering the fever, whereas, with the 
other antipyretics, the sweat comes with the fall. All 
the evidence that we have shows that the course of 
typhoid fever is in no way shortened by the drug. 
These are the facts most generally received, but it is 
but fair to state that other opinions, even of a very 



Salicylic Acid: Clinical Evidence. 15T 

recent date, are held by well-known men. Huchard 1 
uses the salicylate of magnesium with great success in 
typhoid fever, and asserts that 45 to 90 grains in each 
twenty-four hours relieves the ataxic symptoms and 
changes the asthenia into greater strength. Jackson 2 
and King 3 also speak well of the acid under such cir- 
cumstances, and Sullivan 4 regards it as very efficacious. 

In the fever of phthisis the drug has nothing to 
recommend it, and much to condemn its employment, 
as, for example, the profuse sweats, which become worse 
under its influence. The tendency to gastric disorder, 
always present in tuberculosis, is decidedly increased 
by its use. 

Sthenic Fevers. — The contra-indications to the use 
of salicylic acid in these affections are not so pressing 
as in the fevers of an asthenic type, while the sweating- 
is often excessive and even weakening in its results. 
The chief objection is the irritation of the gastric mu- 
cous membrane, and the fact that we have so many 
better remedies of the same class. 

Upon malarial fevers the drug seems to have a slight 
antiperiodic influence. 

Rheumatism. — The employment of salicjdates in 
rheumatism is both for their specific influence and their 
antip} r retic power, yet there are some in the profession 
who, even at the present da}^, would have us believe 
that such a specific action does not exist. There are 
others, too, who assert that the severity of the disease, 
so far as continuances or relapses are concerned, is not 
favorably affected by the drug. Thus, Hood 5 has col- 

1 Journal de Med. de Paris, January 15, 1888. 

2 Medical Standard, March, 1888. 

3 Weekly Medical Review, June 30, 1888. 

4 Medical Standard, March, 1888. 
6 London Lancet, February, 1888. 



158 Fever : its Pathology and Treatment. 

lected the records of over 2000 cases of acute sthenic 
rheumatism of a t} T pical character, more than one-half 
of which were treated by salicylates, and in the analysis 
made by him it appears that while the drug caused a 
decrease in pain and a fall of temperature, its use was 
also followed by more relapses than occur under the 
older methods of treatment, and it left the patients 
much enfeebled. It had no effect whatever over the 
cardiac lesions, and the mortality was in no way 
decreased. 



COLD BATHING. 

From the title prescribed by the Boylston Prize 
Committee it is not to be supposed that the employment 
of the cold pack or bathing is to be considered in the 
treatment of fever in this essay, yet one can scarcely 
pass by this important subject without calling attention 
to its usefulness. 

Used, as was cold bathing, many years before the use 
of antipyretic remedies in fevers, it was at one time in 
great danger of being lost sight of in the struggle for 
internal febrifuges ; yet, no one having large experience 
in hospital or private practice can think but that such 
methods are equal to or more useful than the drugs. 
Cold bathing is a power for good before which every 
other measure must stand aside. 

While such a conclusion is generally accepted to-day 
by almost every one, we have in reality passed through a 
period in which the opinions of many men were greatly 
disturbed and opposed to one another, and von Ziemssen 
has recently put the opinions of all these opposing 
factions in so concise a form that it may be permissible 
to quote him in this place. Speaking of the worth of 
antipyresis in any form, he divides the writers of the 
last twenty years into groups as follows : — 

The extreme hydriaticists, who use only the cold 
bath, and reject internal antipyretics, such as Brandt, 
Yogel, Winternitz, and others. 

The moderate hydriaticists, who resort to lukewarm 
baths, but reject internal antipyretics, among whom may 
be named Naunyn and others. 

Those who, according to indication, resort to moder- 
ate hydrotherapy and to internal antipyretics, such as 
Liebermeister, Jurgensen, and Riess. 

(159) 



160 Fever: its Pathology and Treatment. 

Those who consider fever as a salutary and necessary 
regulator, and only resort to antipyretics when danger- 
ous sj-mptoms arise, as Heubner, Curschmann, and 
others. 

Those who claim that fever is a necessary phenome- 
non, and, therefore, reject all attention to antipyresis 
and attend to diet (Glaser). 

Those who absolutely deny the influence of treat- 
ment on the mortality of fever (Port). 

Truly, it would be hard to find a set of more diverse 
and contradictory opinions in regard to so limited a 
subject ; but, fortunatelv, the practice of Liebermeister, 
Jurgensen, and Riess has virtually proved the value of 
cold, and it is resorted to by most of us. Those who 
have tried it rely on this method very extensively. 

A very important question arises as to the value of 
the cold pack in private practice. There can be no 
doubt of its acting very well if carefully carried out 
under such circumstances. It is certainly much the best 
remedy where trained nurses are at hand to administer 
it, but where only members of the family are to care 
for the sick man, and the doctor can only be on hand 
once in twenty-four hours, it is manifestly impossible to 
use it. Even if the bath be properly given, the ex- 
haustion produced by clumsy handling may overbalance 
all the good to be achieved. 

It has been claimed that the cold pack never results 
in cardiac failure, as does the use of antipyretics. The 
author is quite confident of the fallacy of this statement ; 
indeed, he has but recently seen such a case. The 
cold pack cannot be used any more blindly than the 
antipyretic drug, and it is probable that when this meas- 
ure is more widely employed more reports of untoward 
effects will appear in the medical magazines. 



CONCLUSIONS. 

An essay having a large and extensive bibliography 
is almost useless unless the writer finally gives the 
results reached from his studies in so short, concise, 
and distinct a form as to enable the reader to carry 
away with him a clear conception of the ideas which 
the mass of material should be productive of in his 
thought and practice. 

From the reading of a large amount of literature on 
this subject, the writer thinks it may be stated that anti- 
pyrin stands to-day foremost in the ranks of the anti- 
pyretics, with antifebrin next, while thallin and phenace- 
tine follow, with perhaps a preference for the latter. 
These conclusions are in regard to the reduction of fever. 
In pain the arrangement should be somewhat changed. 
Antipyrin still takes the lead, but phenacetine is quite 
as useful an analgesic as antifebrin, and seems more safe. 
Thallin possesses hardly any such power. 

In rheumatism, of course, the salicylates act better 
than the rest of the class of antipyretics, particularly in 
reference to the pain and the cure of the disease itself, 
but the others control the fever of rheumatism in a 
much more effective manner. 

As a general rule, marked depression and adynamia 
contra-indicate the use of all antipyretic drugs, although 
exceptions to this rule, of course, occur. 

For wide-spread application, to be put in the hands 
of the inexperienced, to be efficacious and yet quite 
harmless, cold sponging is the antipyretic remedy par 
excellence ; but even this must be used carefully and 
with intelligent ideas of its objects and results. The 

Ga (161) 



162 Fever: its Pathology and Treatment. 

greatest enemies of antipyretic treatment are its friends, 
who, in their enthusiasm, often fail to use discretion and 
employ the measures to excess, or without regard to the 
indications really at hand. 

There can be no doubt but that antipyresis is an 
addition to our remedial measures of vast value, and 
the suffering which it relieves is one of the blessings 
which follow increased knowledge and the new era of 
therapeutical training. 



INDEX. 

PAGE 

Absorption of salicylic acid 134 

Acetphenetidine 114 

Acid, salicylic 127 

Action, antiseptic, of antifebrin 82 

Alterations of antifebrin in body 80 

Antifebrin 69 

alterations in body 80 

antiseptic action of 82 

circulation, effect on 72 

clinical evidence 83 

elimination of 80 

effect of, on fevered animals 71 

on circulation 72 

on heat functions 69 

on nervous system 78 

on respiration 79 

on tissue waste 76 

on urine 76 

in nervous diseases 103 

in phthisis 99 

in rheumatism 101 

in typhoid fevers ... 95 

toxic changes produced by 79 

use of, in fever 91 

untoward effects of 84 

Antipyrin 11 

action on nervous system 29 

antipyretic influence of 60 

antiseptic action of 33 

clinical observations about 34 

for chorea 67 

elimination of 32 

experimental studies 11 

general influence of 36 

in malarial fever 65 

in nervous diseases 65 

in pain. 65 

in sun-stroke 63 

in tissue waste 23 

in typhoid fever , 61 

on circulation 18 

on heat functions 11 

on nervous system 29 

toxic effects from prolonged use of. 32 

(163) 



164 Index. 

PAGE 

Antipyretic influence of antipyrin 60 

Antipyretic, salicylic acid as an 155 

Antipyretics 2 

Antiseptic action of antifebrin 82 

action of antipyrin 33 

action of salicylic acid . 137 

power of thallin 107 

Bathing, cold 159 

Blood, effect of antifebrin on 74 

effect of plienacetine on . 115 

Bodily metabolism under antipyrin 23 

under salicylic acid 132 

Calorimeters 7 

Changes, toxic, produced by antifebrin 79 

Chorea, antipyrin for 67 

Circulation, action of thallin on 105 

effect of antifebrin on 72 

effect of antipyrin on 18 

effect of plienacetine on 114 

effect of salicylic acid on 131 

Clinical evidence about antipyrin 34 

concerning antifebrin. 83 

concerning salicylic acid • 139 

in regard to phenacetine 118 

in regard to thallin Ill 

Cold bathing 159 

Conclusions as to the action of phenacetine 117 

as to physiological action of antifebrin 82 

antipyrin 33 

thallin Ill 

drawn from entire essay 161 

Dangers of fever 9 

Effects of antifebrin, untoward 84 

salicylic acid 127 

Elimination of antifebrin 80 

antipyrin 32 

phenacetine 116 

salicylic acid 136 

thallin 109 

Experimental evidence about antifebrin 69 

Fallacious experiments 1 

Fever, antifebrin for 91 

dangers of 9 

Fevers, sthenic, antipyrin in 62 

typhoid, antipyrin in 61 



Index. 165 

PAGE 

Fevers, use of thallin in Ill 

Fevered animals, effect of antifebrin on ... 71 

General influence of antipyrin 36 

Heat functions 5 

effect of antifebrin on 69 

antipyrin on 11 

phenacetine on 114 

salicylic acid on 128 

thallin on 105 

Hyperpyrexia 3 

Influence, general, of antipyrin 36 

Introduction 1 

Malarial fevers, antipyrin in 65 

Metabolism under antipyrin 23 

Nervous diseases, antifebrin for 121 

antipyrin in 65 

phenacetine in 103 

system, action of salicylic acid on 133 

effect of antifebrin on 78 

antipyrin on 29 

phenacetine on 115 

Pain, antipyrin in 65 

Para-amido-phenol-sulphate 80 

Phenacetine 114 

clinical evidence . . 118 

effect on blood 115 

circulation 114 

heat functions 114 

nervous disease 121 

system 115 

urine 116 

elimination of 116 

toxic effects of 117 

Phthisis, antifebrin in 99 

Physiological action of antipyrin, conclusions concerning 33 

action of salicylic acid, conclusions . . 130 

Prolonged use of antifebrin, effect of 79 

Pulse, in relation to fever. . . . 7 

Respiration, effect of antifebrin on 79 

antipyrin on 31 

salicylic acid on 133 

Rheumatism, antifebrin in • 101 

salicylic acid in . .* 157 

Salicylic acid 127 



166 Index. 

« i. ,. .-. , . PAGE 

Salicylic acid, absorption 134 

action on circulation 131 

heat functions 128 

nervous system 133 

respiration 133 

tissue waste 132 

as an antipyretic 155 

as an antiseptic 137 

conclusions as to action of 139 

clinical evidence 139 

elimination of . 130 

in rheumatism 157 

in sthenic fevers 157 

in typhoid fevers 156 

untoward effects of 100 

Sthenic fevers, antifebrin in 100 

antipyrin in 62 

salicylic acid in 157 

Studies, experimental, on antipyrin 11 

Sun-stroke, antipyrin in 63 

Tables of untoward effects 38 

Thallin 105 

antispeptic power of 107 

clinical evidence Ill 

elimination of 109 

on circulation 105 

on heat functions 105 

tissue waste under 109 

toxic effects from 108 

Tissue waste, effect of antifebrin on 76 

under antipyrin . 23 

under salicylic acid. 132 

under thallin. 109 

Toxic changes produced by antifebrin 79 

effects of phenacetine . 117 

from prolonged use of antipyrin 32 

thallin 108 

Typhoid fever, antifebrin in 95 

antipyrin in 65 

salicylic acid in ...... 156 

Untoward effects of antifebrin „ 84 

antipyrin 37 

salicylic acid . 140 

Urine, effects of antifebrin on. 76 

phenacetine on 116 

Use of antifebrin in fever 91 

Waste, tissue, effect of antifebrin on 76 






8 ' .* 




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I^Kl 



